RARE DISEASE
Leigh syndrome
Leigh syndrome
Leigh syndrome
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Drug discovery
10
drugs
With orphan designations
Overview
Leigh syndrome is a genetically heterogeneous mitochondrial disorder characterized by neuroregression, symmetric brainstem/basal ganglia lesions, and impaired oxidative phosphorylation. Typically presenting in infancy with feeding difficulties, ataxia, and hypotonia, it progresses to respiratory failure, with most patients surviving <3 years [1][6][9]. Diagnosis requires clinical features plus biochemical/genetic evidence of mitochondrial dysfunction [1][9].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
484 drug discovery papers about Leigh syndrome, with 2 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
484 drug discovery papers about Leigh syndrome, with 2 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-21 | Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking. We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed. Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1). Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
2026-07-17 | A phase III double-blind, placebo-controlled, randomized withdrawal trial of 5‑aminolevulinic acid hydrochloride with sodium ferrous citrate for efficacy and safety in patients diagnosed as Leigh syndrome.
A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP‑004 (5‑aminolevulinic acid hydrochloride and sodium ferrous citrate) was conducted to confirm the efficacy and safety of SPP-004 for maintenance of clinical response in patients diagnosed with Leigh syndrome (LS) showing central nervous system disorders. Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients who showed improvement on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP‑004 or placebo (n = 14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB‑period (SPP-004 n = 13, Placebo n = 14) and the entire study period (n = 54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group showed maintained efficacy (p = 0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS patients who achieved an initial clinical response.
2026-07-13 | Navigating the Mitochondrial Maze: A Case Report of Emergent Cesarean Delivery After Labor Induction in a Patient With Leigh Syndrome.
Leigh syndrome is a rare mitochondrial disorder characterized by progressive psychomotor regression. Due to high childhood mortality and rare adult-onset cases, there are no guidelines for the obstetric management of this population. In these patients, physiological stress from labor may precipitate acute decompensation, manifesting with metabolic acidosis and multiorgan failure. We report the obstetric anesthetic management of a patient with adult-onset Leigh syndrome who required an emergent intrapartum cesarean delivery after labor induction. This case highlights the necessity of tailored anesthetic strategies to mitigate mitochondrial dysfunction and supports the potential safety of essential peripartum medications previously undocumented in this population.
2026-07-10 | An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
proteins
2025-09-19 | AMPD2 deficiency implicates cytosolic purine metabolism in the pathogenesis of Leigh syndrome
Abstract Importance Cellular mechanisms underlying mitochondrial dysfunction, a hallmark feature of many neurodegenerative conditions, remain incompletely understood, and their true diversity is unknown. Objective To identify and functionally validate novel genetic variants causative of Leigh syndrome. Design We performed whole genome sequencing (WGS) and first-degree relative genotyping on two unrelated adult subjects with brain MRI abnormalities evoking Leigh syndrome. Blue native polyacrylamide gel electrophoresis (BN-PAGE) and respiratory chain enzymatic activity assays were performed to screen for respiratory complex assembly and/or oxidative phosphorylation impairments. Cells obtained from patient dermal and muscular biopsies were immortalized and later genetically corrected to evaluate cellular response to metabolic stress. Setting Subjects were recruited from The Neuro (McGill University), Rizk Hospital (Lebanese American University), and Centre Hospitalier Universitaire Sainte-Justine (University of Montreal). Research connections were established through the White Matter Rounds Network and GeneMatcher. Participants Four subjects representing three families with undiagnosed Leigh syndrome (age range 10-40 years) were ultimately recruited. Main outcome(s) and Measure(s) DNA sequencing uncovered a new autosomal recessive Leigh syndrome-associated gene that was functionally validated. Results Bi-allelic pathogenic variants in AMPD2 were detected in all subjects. BN-PAGE of patient skeletal muscle mitochondria captured an isolated complex V assembly defect in the context of heavy mTOR activation, while the accompanying enzymological assays reported decreased activities of complexes I and IV. Opposite to controls, patient-derived cell lines and muscle lacked AMPD2 protein, attributing null status to the variants detected. During metabolic challenge, only mutant cells suffered from mitochondrial hyperfusion and high-order cytosolic IMPDH2 oligomerization, implying simultaneous ATP accumulation and GTP deficiency. However, under these conditions, both complex V assembly and mTOR status in mutant cells and myotubes remained unchanged relative to the corrected lines. All mutant phenotypes observed collectively reverted upon exogenous introduction of wild-type AMPD2. Conclusions and Relevance The recognition of AMPD2 -related Leigh syndrome ( AMPD2 -LS) as a novel entity provides strong evidence for classifying AMPD2 deficiency as a mitochondrial disease. Our data suggest that respiratory capacity is significantly modulated by AMPD2, a cytosolic enzyme selectively regulating complex V assembly through an elusive process. Key points Question Do AMPD2 mutations cause mitochondrial disease? Findings In this case series, we found that four subjects from three families with molecularly unexplained Leigh syndrome carried bi-allelic, loss-of-function variants in AMPD2 , a gene not previously linked to mitochondrial disease. Biochemical analyses uncovered an isolated complex V assembly defect, providing diagnostic confirmation of a new entity: AMPD2 -related Leigh syndrome ( AMPD2 -LS). Meaning The cytosolic purine cycle is a primordial determinant of oxidative phosphorylation and mitochondrial health.
2024-10-13 | Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype (WT) mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions. Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SIGNIFICANCE: The Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.
2024-07-19 | Phenotypic Assessment of Cox10 Variants and their Implications for Leigh Syndrome
Objectives Cox10 is an enzyme required for the activity of cytochrome c oxidase. Humans who lack at least one functional copy of Cox10 have a form of Leigh Syndrome, a genetic disease that is usually fatal in infancy. As more human genomes are sequenced, new alleles are being discovered; whether or not these alleles encode functional proteins remains unclear. Thus, we set out to measure the phenotypes of many human Cox10 variants by expressing them in yeast cells. Results We successfully expressed the reference sequence and 25 variants of human Cox10 in yeast. We quantitated the ability of these variants to support growth on nonfermentable media and directly measured cytochrome c oxidase activity. 11 of these Cox10 variants supported approximately half or more the cytochrome c oxidase activity compared to the reference sequence. All of the strains containing those 11 variants also grew robustly using a nonfermentable carbon source. Cells expressing the other variants showed low cytochrome c oxidase activity and failed to grow on nonfermentable media.
2024-07-18 | Infantile Epileptic Spasms Syndrome Complicated by Leigh Syndrome and Leigh-Like Syndrome: A Retrospective, Nationwide, Multicenter Case Series.
Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS). We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events. The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs. ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient.
2022-10-07 | Communication between the nucleus and the mitochondria via NDUFS4 alternative splicing in gastric cancer cells
Abstract A constant communication between the nucleus and the mitochondria allows both organelles to ensure cellular homeostasis and adaptation to mitochondrial stress. Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving a large number of nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct subsets of genes in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic analyses and RNA-seq profiles of IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I subunit NDUFS4 and downregulates a subset of complex I subunits. In IQGAP1 KO cells, respiratory complex I intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial complex I activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 partially restores NDUFS4 AS pattern and expression and reverses mitochondrial defects of IQGAP1 KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of complex I activity through AS regulation.
gene therapies
2026-06-19 | Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
To systematically characterize the phenotypic spectrum, neuroimaging features, heteroplasmy-phenotype correlation, and prognosis of the m.10191 T > C mutation. We collected and analyzed data from 52 patients (14 newly recruited; 38 from literature). Phenotypes were pre-classified as Leigh syndrome (LS), Leigh-like syndrome (LLS), MELAS/LS overlap syndrome, and MELAS-like syndrome. Neuroimaging data were subjected to statistical analysis to explore inter-lesional associations and lesion-symptom correlations. Heteroplasmy level underwent k-means clustering and latent class analysis (LCA) to define data-driven subgroups and model genotype-phenotype correlations. Prognostic factors were evaluated through Bayesian logistic regression, and survival analysis was conducted. The cohort exhibited phenotypic heterogeneity, dominated by LS (46.2%). Key features included epilepsy, developmental delay, and dystonia. Globus pallidus involvement frequently co-occurred with midbrain and pontine lesions. Heteroplasmy level differed significantly across phenotypes. LCA identified three classes corresponding to clinical phenotypes. High heteroplasmy level, medullary involvement, and severe hyperlactatemia were associated with disease progression. Survival analysis indicated a 5 year survival rate of 80.0%, with high heteroplasmy level, hypotonia, and cerebellar lesions predicting poorer survival. The m.10191 T > C mutation is linked to a continuous clinical spectrum correlated with heteroplasmy level. Specific clinical and neuroimaging features serve as valuable biomarkers for phenotypic classification and prognostic assessment.
2026-03-15 | Leigh syndrome – review
Leigh syndrome is a rare, progressive mitochondrial disorder with onset typically in early infancy, characterized by severe neurodegeneration and high mortality. Its etiology is genetically heterogeneous and includes pathogenic variants in both mitochondrial and nuclear DNA, leading to impaired respiratory chain function and oxidative phosphorylation. The clinical phenotype encompasses a broad spectrum of neurological and systemic manifestations, with characteristic bilateral lesions of the basal ganglia and brainstem on magnetic resonance imaging serving as a key diagnostic feature. This review summarizes current knowledge on the pathogenesis, genotype–phenotype correlations, clinical features, and diagnostic approach in Leigh syndrome, with particular emphasis on the role of molecular genetic testing. The challenges and possibilities of genetic counseling and prenatal diagnosis, as well as current therapeutic strategies, are also discussed.
2026-03-02 | New Neuroimaging Findings in Enoyl-CoA Hydratase Short-Chain 1 (ECHS1) Deficiency.
Enoyl-CoA hydratase short-chain 1 (ECHS1) variants are among the most common causes of Leigh syndrome. A five-year-old boy with ECHS1 deficiency initially presented with acute encephalopathy during the neonatal period. The patient had a high serum lactate level and a normal lactate/pyruvate ratio. Diffusion-weighted imaging showed reduced diffusion in the peri-rolandic subcortical white matter on day 3 and in the entire cortex and subcortical white matter on day 7. The patient subsequently presented with poor feeding, hypotonia, nystagmus, cerebellar ataxia, hearing loss, and strabismus. At one year of age, neuroimaging revealed reduced diffusion, hyperperfusion on arterial spin labeling, and increased lactate on magnetic resonance (MR) spectroscopy in the cerebellum. Cerebellar lesions have not previously been reported as imaging findings of ECHS1 deficiency except in one previous report of a patient with the same ECHS1 variant. Therefore, the ECHS1variant may specifically involve the cerebellum.
2026-01-23 | Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.
Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.
2026-01-01 | Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.
cell therapies
2026-05-25 | Metabolic Reprogramming and Exosome Remodeling in an Ndufs4 ‐Deficient Model of Leigh Syndrome
ABSTRACT Leigh syndrome is a severe neurometabolic disorder with an incompletely understood pathogenesis. This study investigated the role of Ndufs4 knockout in Leigh syndrome by exploring its impact on cellular metabolism and exosome biology. Initially, we observed that homozygous knockout ( Ndufs4 −/− ) mice exhibited significantly reduced body size and spleen weight compared to wild‐type ( Ndufs4 +/+ ) controls, although the spleen index remained unchanged. Notably, the brain index was significantly increased. Histological analysis revealed structural abnormalities in brain tissue, accompanied by elevated expression of the astrocytic marker GFAP, both in vivo and in differentiated neural stem cells (NSCs), indicating a neuropathological effect of Ndufs4 knockout. Metabolically, Ndufs4 knockout in NSCs did not reduce ATP levels but increased reactive oxygen species (ROS) levels, enhanced glucose uptake (2‐NBDG), and decreased mitochondrial membrane potential (JC‐1). Concurrent shifts in metabolites—decreased L‐lactate, increased acetyl‐CoA, and a lower NADP + /NADPH ratio—implied a potential redirection of metabolic flux toward the pentose phosphate pathway. Furthermore, although the total exosome concentration was reduced in Ndufs4 −/− mice, the protein content per exosome was significantly elevated, indicating enhanced protein loading per vesicle. Proteomic profiling of brain‐derived exosomes identified increased levels of flotillin‐1 and Slc6a5, proteins associated with the mTOR pathway. Consistent with this, downstream mTOR signaling (Phospho‐S6 Ribosomal Protein (Ser235/236; p‐RPS6) and Phospho‐p70 S6 kinase (Thr389; p‐p70S6K)) was substantially attenuated in Ndufs4 −/− mice, indicating suppression of the mTOR pathway. Together, these results elucidate novel mechanisms through which Ndufs4 knockout drives exosomal remodeling, reprograms cellular metabolism, and suppresses mTOR signaling, providing a conceptual framework for understanding Leigh syndrome pathogenesis and informing therapeutic development.
2026-03-20 | Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.
2025-01-09 | [Study of the feasibility of polar body transfer combined with preimplantation genetic testing for blocking the intergenerational transmission of mitochondrial genetic diseases].
To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation. A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MII oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12). An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MII were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39+5 weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples. The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.
2024-09-03 | Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
2024-08-06 | A Method for Producing Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Leigh Syndrome Patients for Its Application in Disease Modeling and Drug Validation.
Leigh syndrome (LS), a complex multisystemic disorder, poses significant challenges in genetic medicine due to its intricate pathogenesis and wide-ranging clinical manifestations. Notably, these arise from mutations in either nuclear genetic DNA or mitochondrial DNA, affecting ATP production and resulting in diverse clinical outcomes. The unpredictable trajectory of this disease, ranging from severe developmental delays to early mortality, underscores the need for improved therapeutic solutions. This research pivots toward the novel use of induced pluripotent stem cells (iPSCs) as a promising platform for understanding disease mechanisms and spearheading patient-specific drug discoveries. Given the past successes of iPSCs in delineating organ-specific disorders and the recent endorsement of human iPSC-derived cardiomyocytes (CMs) by the FDA for drug evaluation, our work seeks to bridge this innovation to Leigh syndrome research. We detail a methodological approach to generate iPSCs from LS patients and differentiate them into iPSCs-CMs. Using multi-electrode array (MEA) analyses, we evaluate the field potential of these cells, spotlighting the potential of hiPSC-CM in drug validation and disease modeling. This pioneering approach offers a glimpse into the future of patient-centric therapeutic interventions for Leigh/Leigh-like syndrome.
other
2026-02-04 | Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.
Although recent evidence suggests that the immune system contributes to the pathogenesis of paediatric Leigh syndrome, detailed mechanistic insights are still lacking. Here, we investigated the involvement of immune system activation and inflammation in brain tissue in Leigh syndrome, using hypothesis generating methods. We compared the transcriptomes of olfactory bulb and cerebellum from male Ndufs4−/− (knockout) mice (n = 5–6), a well-established model of paediatric Leigh syndrome. Relative to wildtype animals, knockout mice displayed enrichment of innate immune system pathways in the olfactory bulb. Unexpectedly, relative to the olfactory bulb, few pathways were enriched in the cerebellum, and none that indicated similar changes to the immune system. Innate immune system pathways in the olfactory bulb were mainly upregulated and included a large set of interferon stimulated genes, and genes involved in JAK-STAT and retinoic acid-inducible gene 1-like signalling, interleukins, interferon receptors and endogenous double strand RNA sensors. We propose that innate immune system activation starts in the olfactory bulb, is mediated by the retinoic acid-inducible gene 1-like signalling pathway in response to increased cytosolic double-strand RNA, leading to chemokines that recruit leukocytes to other brain regions to elicit an immune response. Our results fill in the gap between mitochondrial dysfunction and activation of the innate immune response, which has been reported by others. Our findings strongly suggest that immune system activation constitutes part of the Leigh syndrome pathomechanism, which is compatible with the improvement observed in mitochondrial disease patients following immune system-targeting interventions.
2024-04-29 | Interferon-gamma contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome.
Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS. To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS. Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition. IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.
2023-07-10 | IFNγ modestly contributes to disease progression in theNdufs4(-/-) model of Leigh syndrome while IP10 is dispensable
Abstract Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disease characterized by severe neurologic and metabolic abnormalities. The defining feature of the disease is the presence of symmetric, bilateral, progressive necrotizing lesions in the brain stem, cerebellum, and basal ganglia. The pathogenic mechanisms underlying disease initiation and progression in LS have yet to be elucidated. Recent evidence demonstrates that the immune system plays a key role in LS pathogenesis. Treatment with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease in the Ndufs4 (-/-) mouse model of LS, but the mechanisms leading to immune activation and governing disease progression remain to be elucidated. In recent work, the cytokines IFNγ and IFNγ-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4 (-/-) brainstem. Given their role as macrophage-activating factors, here we sought to assess the role of IFNγ and IP10 in LS using by generating Ndufs4 (-/-)/ Ifng (-/-) and Ndufs4 (-/-)/ IP10 (-/-) double knockout lines. We find that IP10 alone does not significantly impact the onset or progression of disease in the Ndufs4 (-/-) model, while IFNγ loss significantly, but modestly, improves survival. These data indicate that IFNγ contributes to pathology, but that IFNγ and IP10 are both dispensable for overall disease course of LS. Our findings support some role for IFNγ targeting therapies in the management of mitochondrial disease, but suggest they may provide only modest benefits, at least in LS.
2023-02-03 | PET117 Modulates Mitochondrial-encoded COX1 Translation by stabilizing TACO1
Abstract Mitochondria are the most important organelles in energy metabolism. Complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are formed by proteins of dual origin synthesized in the cytosol or mitochondria. The mechanisms underlying specific translation by mitoribosomes in mammals are largely unknown. Here, we report a chaperone protein of cytochrome c oxidase (COX) assembly, PET117 plays a critical role in the synthesis of mitochondrial-encoded COX1 protein in human cells. Lack of PET117 impaired mitochondrial function via suppression of mitochondrial oxygen consumption rate (OCR), probably due to reduced stability of TACO1, a COX1 translational activator. We uncovered the role of PET117 in mitochondrial regulation and a novel PET117-TACO1 axis modulating mitochondrial gene expression.
2022-09-08 | The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.
Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms. Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents. In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4(KO) model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease. Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease. Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.
small molecules
2026-07-21 | Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking. We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed. Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1). Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
2026-07-17 | A phase III double-blind, placebo-controlled, randomized withdrawal trial of 5‑aminolevulinic acid hydrochloride with sodium ferrous citrate for efficacy and safety in patients diagnosed as Leigh syndrome.
A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP‑004 (5‑aminolevulinic acid hydrochloride and sodium ferrous citrate) was conducted to confirm the efficacy and safety of SPP-004 for maintenance of clinical response in patients diagnosed with Leigh syndrome (LS) showing central nervous system disorders. Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients who showed improvement on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP‑004 or placebo (n = 14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB‑period (SPP-004 n = 13, Placebo n = 14) and the entire study period (n = 54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group showed maintained efficacy (p = 0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS patients who achieved an initial clinical response.
2026-07-13 | Navigating the Mitochondrial Maze: A Case Report of Emergent Cesarean Delivery After Labor Induction in a Patient With Leigh Syndrome.
Leigh syndrome is a rare mitochondrial disorder characterized by progressive psychomotor regression. Due to high childhood mortality and rare adult-onset cases, there are no guidelines for the obstetric management of this population. In these patients, physiological stress from labor may precipitate acute decompensation, manifesting with metabolic acidosis and multiorgan failure. We report the obstetric anesthetic management of a patient with adult-onset Leigh syndrome who required an emergent intrapartum cesarean delivery after labor induction. This case highlights the necessity of tailored anesthetic strategies to mitigate mitochondrial dysfunction and supports the potential safety of essential peripartum medications previously undocumented in this population.
2026-07-10 | An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
proteins
2025-09-19 | AMPD2 deficiency implicates cytosolic purine metabolism in the pathogenesis of Leigh syndrome
Abstract Importance Cellular mechanisms underlying mitochondrial dysfunction, a hallmark feature of many neurodegenerative conditions, remain incompletely understood, and their true diversity is unknown. Objective To identify and functionally validate novel genetic variants causative of Leigh syndrome. Design We performed whole genome sequencing (WGS) and first-degree relative genotyping on two unrelated adult subjects with brain MRI abnormalities evoking Leigh syndrome. Blue native polyacrylamide gel electrophoresis (BN-PAGE) and respiratory chain enzymatic activity assays were performed to screen for respiratory complex assembly and/or oxidative phosphorylation impairments. Cells obtained from patient dermal and muscular biopsies were immortalized and later genetically corrected to evaluate cellular response to metabolic stress. Setting Subjects were recruited from The Neuro (McGill University), Rizk Hospital (Lebanese American University), and Centre Hospitalier Universitaire Sainte-Justine (University of Montreal). Research connections were established through the White Matter Rounds Network and GeneMatcher. Participants Four subjects representing three families with undiagnosed Leigh syndrome (age range 10-40 years) were ultimately recruited. Main outcome(s) and Measure(s) DNA sequencing uncovered a new autosomal recessive Leigh syndrome-associated gene that was functionally validated. Results Bi-allelic pathogenic variants in AMPD2 were detected in all subjects. BN-PAGE of patient skeletal muscle mitochondria captured an isolated complex V assembly defect in the context of heavy mTOR activation, while the accompanying enzymological assays reported decreased activities of complexes I and IV. Opposite to controls, patient-derived cell lines and muscle lacked AMPD2 protein, attributing null status to the variants detected. During metabolic challenge, only mutant cells suffered from mitochondrial hyperfusion and high-order cytosolic IMPDH2 oligomerization, implying simultaneous ATP accumulation and GTP deficiency. However, under these conditions, both complex V assembly and mTOR status in mutant cells and myotubes remained unchanged relative to the corrected lines. All mutant phenotypes observed collectively reverted upon exogenous introduction of wild-type AMPD2. Conclusions and Relevance The recognition of AMPD2 -related Leigh syndrome ( AMPD2 -LS) as a novel entity provides strong evidence for classifying AMPD2 deficiency as a mitochondrial disease. Our data suggest that respiratory capacity is significantly modulated by AMPD2, a cytosolic enzyme selectively regulating complex V assembly through an elusive process. Key points Question Do AMPD2 mutations cause mitochondrial disease? Findings In this case series, we found that four subjects from three families with molecularly unexplained Leigh syndrome carried bi-allelic, loss-of-function variants in AMPD2 , a gene not previously linked to mitochondrial disease. Biochemical analyses uncovered an isolated complex V assembly defect, providing diagnostic confirmation of a new entity: AMPD2 -related Leigh syndrome ( AMPD2 -LS). Meaning The cytosolic purine cycle is a primordial determinant of oxidative phosphorylation and mitochondrial health.
2024-10-13 | Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype (WT) mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions. Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SIGNIFICANCE: The Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.
2024-07-19 | Phenotypic Assessment of Cox10 Variants and their Implications for Leigh Syndrome
Objectives Cox10 is an enzyme required for the activity of cytochrome c oxidase. Humans who lack at least one functional copy of Cox10 have a form of Leigh Syndrome, a genetic disease that is usually fatal in infancy. As more human genomes are sequenced, new alleles are being discovered; whether or not these alleles encode functional proteins remains unclear. Thus, we set out to measure the phenotypes of many human Cox10 variants by expressing them in yeast cells. Results We successfully expressed the reference sequence and 25 variants of human Cox10 in yeast. We quantitated the ability of these variants to support growth on nonfermentable media and directly measured cytochrome c oxidase activity. 11 of these Cox10 variants supported approximately half or more the cytochrome c oxidase activity compared to the reference sequence. All of the strains containing those 11 variants also grew robustly using a nonfermentable carbon source. Cells expressing the other variants showed low cytochrome c oxidase activity and failed to grow on nonfermentable media.
2024-07-18 | Infantile Epileptic Spasms Syndrome Complicated by Leigh Syndrome and Leigh-Like Syndrome: A Retrospective, Nationwide, Multicenter Case Series.
Six percent of patients with Leigh syndrome (LS) present with infantile epileptic spasms syndrome (IESS). However, treatment strategies for IESS with LS remain unclear. This retrospective study aimed to evaluate the efficacy and safety of treatment strategies in patients with IESS complicated by LS and Leigh-like syndrome (LLS). We distributed questionnaires to 750 facilities in Japan, and the clinical data of 21 patients from 15 hospitals were collected. The data comprised treatment strategies, including adrenocorticotropic hormone (ACTH) therapy, ketogenic diet (KD) therapy, and antiseizure medications (ASMs); effectiveness of each treatment; and the adverse events. The median age at LS and LLS diagnosis was 7 months (range: 0 to 50), whereas that at the onset of epileptic spasms was 7 (range: 3 to 20). LS was diagnosed in 17 patients and LLS in four patients. Seven, two, five, and seven patients received ACTH + ASMs, ACTH + KD + ASMs, KD + ASMs, and ASMs only, respectively. Four (44%) of nine patients treated with ACTH and one (14%) of seven patients treated with KD achieved electroclinical remission within one month of treatment. No patients treated with only ASMs achieved electroclinical remission. Seven patients (33%) achieved electroclinical remission by the last follow-up. Adverse events were reported in four patients treated with ACTH, none treated with KD therapy, and eight treated with ASMs. ACTH therapy shows the best efficacy and rapid action in patients with IESS complicated by LS and LLS. The effectiveness of KD therapy and ASMs in this study was insufficient.
2022-10-07 | Communication between the nucleus and the mitochondria via NDUFS4 alternative splicing in gastric cancer cells
Abstract A constant communication between the nucleus and the mitochondria allows both organelles to ensure cellular homeostasis and adaptation to mitochondrial stress. Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving a large number of nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct subsets of genes in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic analyses and RNA-seq profiles of IQGAP1 KO and parental cells show that IQGAP1 KO alters a specific AS event of the mitochondrial respiratory chain complex I subunit NDUFS4 and downregulates a subset of complex I subunits. In IQGAP1 KO cells, respiratory complex I intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial complex I activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 partially restores NDUFS4 AS pattern and expression and reverses mitochondrial defects of IQGAP1 KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of complex I activity through AS regulation.
gene therapies
2026-06-19 | Clinical Spectrum, Heteroplasmy-Phenotype Correlation, and Prognosis of the MT-ND3 m.10191 T > C Mutation.
To systematically characterize the phenotypic spectrum, neuroimaging features, heteroplasmy-phenotype correlation, and prognosis of the m.10191 T > C mutation. We collected and analyzed data from 52 patients (14 newly recruited; 38 from literature). Phenotypes were pre-classified as Leigh syndrome (LS), Leigh-like syndrome (LLS), MELAS/LS overlap syndrome, and MELAS-like syndrome. Neuroimaging data were subjected to statistical analysis to explore inter-lesional associations and lesion-symptom correlations. Heteroplasmy level underwent k-means clustering and latent class analysis (LCA) to define data-driven subgroups and model genotype-phenotype correlations. Prognostic factors were evaluated through Bayesian logistic regression, and survival analysis was conducted. The cohort exhibited phenotypic heterogeneity, dominated by LS (46.2%). Key features included epilepsy, developmental delay, and dystonia. Globus pallidus involvement frequently co-occurred with midbrain and pontine lesions. Heteroplasmy level differed significantly across phenotypes. LCA identified three classes corresponding to clinical phenotypes. High heteroplasmy level, medullary involvement, and severe hyperlactatemia were associated with disease progression. Survival analysis indicated a 5 year survival rate of 80.0%, with high heteroplasmy level, hypotonia, and cerebellar lesions predicting poorer survival. The m.10191 T > C mutation is linked to a continuous clinical spectrum correlated with heteroplasmy level. Specific clinical and neuroimaging features serve as valuable biomarkers for phenotypic classification and prognostic assessment.
2026-03-15 | Leigh syndrome – review
Leigh syndrome is a rare, progressive mitochondrial disorder with onset typically in early infancy, characterized by severe neurodegeneration and high mortality. Its etiology is genetically heterogeneous and includes pathogenic variants in both mitochondrial and nuclear DNA, leading to impaired respiratory chain function and oxidative phosphorylation. The clinical phenotype encompasses a broad spectrum of neurological and systemic manifestations, with characteristic bilateral lesions of the basal ganglia and brainstem on magnetic resonance imaging serving as a key diagnostic feature. This review summarizes current knowledge on the pathogenesis, genotype–phenotype correlations, clinical features, and diagnostic approach in Leigh syndrome, with particular emphasis on the role of molecular genetic testing. The challenges and possibilities of genetic counseling and prenatal diagnosis, as well as current therapeutic strategies, are also discussed.
2026-03-02 | New Neuroimaging Findings in Enoyl-CoA Hydratase Short-Chain 1 (ECHS1) Deficiency.
Enoyl-CoA hydratase short-chain 1 (ECHS1) variants are among the most common causes of Leigh syndrome. A five-year-old boy with ECHS1 deficiency initially presented with acute encephalopathy during the neonatal period. The patient had a high serum lactate level and a normal lactate/pyruvate ratio. Diffusion-weighted imaging showed reduced diffusion in the peri-rolandic subcortical white matter on day 3 and in the entire cortex and subcortical white matter on day 7. The patient subsequently presented with poor feeding, hypotonia, nystagmus, cerebellar ataxia, hearing loss, and strabismus. At one year of age, neuroimaging revealed reduced diffusion, hyperperfusion on arterial spin labeling, and increased lactate on magnetic resonance (MR) spectroscopy in the cerebellum. Cerebellar lesions have not previously been reported as imaging findings of ECHS1 deficiency except in one previous report of a patient with the same ECHS1 variant. Therefore, the ECHS1variant may specifically involve the cerebellum.
2026-01-23 | Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.
Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.
2026-01-01 | Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.
cell therapies
2026-05-25 | Metabolic Reprogramming and Exosome Remodeling in an Ndufs4 ‐Deficient Model of Leigh Syndrome
ABSTRACT Leigh syndrome is a severe neurometabolic disorder with an incompletely understood pathogenesis. This study investigated the role of Ndufs4 knockout in Leigh syndrome by exploring its impact on cellular metabolism and exosome biology. Initially, we observed that homozygous knockout ( Ndufs4 −/− ) mice exhibited significantly reduced body size and spleen weight compared to wild‐type ( Ndufs4 +/+ ) controls, although the spleen index remained unchanged. Notably, the brain index was significantly increased. Histological analysis revealed structural abnormalities in brain tissue, accompanied by elevated expression of the astrocytic marker GFAP, both in vivo and in differentiated neural stem cells (NSCs), indicating a neuropathological effect of Ndufs4 knockout. Metabolically, Ndufs4 knockout in NSCs did not reduce ATP levels but increased reactive oxygen species (ROS) levels, enhanced glucose uptake (2‐NBDG), and decreased mitochondrial membrane potential (JC‐1). Concurrent shifts in metabolites—decreased L‐lactate, increased acetyl‐CoA, and a lower NADP + /NADPH ratio—implied a potential redirection of metabolic flux toward the pentose phosphate pathway. Furthermore, although the total exosome concentration was reduced in Ndufs4 −/− mice, the protein content per exosome was significantly elevated, indicating enhanced protein loading per vesicle. Proteomic profiling of brain‐derived exosomes identified increased levels of flotillin‐1 and Slc6a5, proteins associated with the mTOR pathway. Consistent with this, downstream mTOR signaling (Phospho‐S6 Ribosomal Protein (Ser235/236; p‐RPS6) and Phospho‐p70 S6 kinase (Thr389; p‐p70S6K)) was substantially attenuated in Ndufs4 −/− mice, indicating suppression of the mTOR pathway. Together, these results elucidate novel mechanisms through which Ndufs4 knockout drives exosomal remodeling, reprograms cellular metabolism, and suppresses mTOR signaling, providing a conceptual framework for understanding Leigh syndrome pathogenesis and informing therapeutic development.
2026-03-20 | Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.
2025-01-09 | [Study of the feasibility of polar body transfer combined with preimplantation genetic testing for blocking the intergenerational transmission of mitochondrial genetic diseases].
To assess the feasibility of first polar body transfer (PB1T) combined with preimplantation mitochondrial genetic testing for blocking the transmission of a pathogenic mitochondrial DNA 8993T>G mutation. A Chinese family affected with Leigh syndrome which had attended the Reproductive Medicine Centre of the First Affiliated Hospital of Anhui Medical University in September 2021 was selected as the study subject. Controlled ovarian hyperstimulation was carried out for the proband after completing the detection of the mitochondrial DNA 8993T>G mutation load among the pedigree members. Mature MII oocytes were inseminated by intracytoplasmic sperm injection (ICSI), cultured in vitro for 5 to 6 days to the blastocyst stage, and trophoblastocytes were obtained by microbiopsy. Mitochondrial DNA testing (PGT-MT) and chromosomal aneuploidy (PGT-A) analyses were carried out after whole-genome amplification, and the embryos with zero mutation load were selected for transfer. Amniotic fluid and umbilical cord blood samples were collected during middle pregnancy and after birth respectively for mitochondrial DNA testing to verify the reliability of embryo screening. As an attempt, PB1 with good morphology of MII oocytes was selected for transfer into the enucleated oocytoplasm from healthy donors, followed by ICSI fertilization, blastocyst culture and PGT of embryos using the same procedure. This study has been approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (No. 2021zhyx-B12). An antagonist protocol was used for ovarian stimulation, and a total of 19 oocytes were obtained, of which 14 MII were fertilized by ICSI, and 2 had developed into blastocysts. PGT-MT was carried out on biopsied trophoblastocytes, in which the mitochondrial DNA 8993T>G mutation load was not detected in one embryo, the other was 100% mutated, and the mutation loads of the remaining unfertilized eggs and developmentally arrested embryos ranged from 0% ~ 100%, presenting a clear biased distribution. With fully informed consent, one PGT-MT zero mutation load blastocyst was transferred and clinical pregnancy was achieved. Mitochondrial DNA and chromosomal testing of amniotic fluid cells during middle pregnancy had revealed no abnormalities. The proband had delivered a healthy boy through Caesarean section at 39+5 weeks of gestation, and no mutation was detected in the cord blood sample. Five well-formed PBs from 14 eggs were selected for PB1 transfer, followed by ICSI and culture, and two of the reconstituted embryos had formed blastocysts, with none of the above mutations detected in the biopsied samples. The PGT-MT technology can help families affected with mitochondrial diseases to have healthy offspring. PB1 transfer in combination with ICSI and PGT-MT holds the promise of turning waste into treasure and providing an alternative means of fertility for such families.
2024-09-03 | Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.
Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.
2024-08-06 | A Method for Producing Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Leigh Syndrome Patients for Its Application in Disease Modeling and Drug Validation.
Leigh syndrome (LS), a complex multisystemic disorder, poses significant challenges in genetic medicine due to its intricate pathogenesis and wide-ranging clinical manifestations. Notably, these arise from mutations in either nuclear genetic DNA or mitochondrial DNA, affecting ATP production and resulting in diverse clinical outcomes. The unpredictable trajectory of this disease, ranging from severe developmental delays to early mortality, underscores the need for improved therapeutic solutions. This research pivots toward the novel use of induced pluripotent stem cells (iPSCs) as a promising platform for understanding disease mechanisms and spearheading patient-specific drug discoveries. Given the past successes of iPSCs in delineating organ-specific disorders and the recent endorsement of human iPSC-derived cardiomyocytes (CMs) by the FDA for drug evaluation, our work seeks to bridge this innovation to Leigh syndrome research. We detail a methodological approach to generate iPSCs from LS patients and differentiate them into iPSCs-CMs. Using multi-electrode array (MEA) analyses, we evaluate the field potential of these cells, spotlighting the potential of hiPSC-CM in drug validation and disease modeling. This pioneering approach offers a glimpse into the future of patient-centric therapeutic interventions for Leigh/Leigh-like syndrome.
other
2026-02-04 | Leigh Syndrome Pathomechanism Involves Region-Specific Innate Immune Activation in Ndufs4 Knockout Mice.
Although recent evidence suggests that the immune system contributes to the pathogenesis of paediatric Leigh syndrome, detailed mechanistic insights are still lacking. Here, we investigated the involvement of immune system activation and inflammation in brain tissue in Leigh syndrome, using hypothesis generating methods. We compared the transcriptomes of olfactory bulb and cerebellum from male Ndufs4−/− (knockout) mice (n = 5–6), a well-established model of paediatric Leigh syndrome. Relative to wildtype animals, knockout mice displayed enrichment of innate immune system pathways in the olfactory bulb. Unexpectedly, relative to the olfactory bulb, few pathways were enriched in the cerebellum, and none that indicated similar changes to the immune system. Innate immune system pathways in the olfactory bulb were mainly upregulated and included a large set of interferon stimulated genes, and genes involved in JAK-STAT and retinoic acid-inducible gene 1-like signalling, interleukins, interferon receptors and endogenous double strand RNA sensors. We propose that innate immune system activation starts in the olfactory bulb, is mediated by the retinoic acid-inducible gene 1-like signalling pathway in response to increased cytosolic double-strand RNA, leading to chemokines that recruit leukocytes to other brain regions to elicit an immune response. Our results fill in the gap between mitochondrial dysfunction and activation of the innate immune response, which has been reported by others. Our findings strongly suggest that immune system activation constitutes part of the Leigh syndrome pathomechanism, which is compatible with the improvement observed in mitochondrial disease patients following immune system-targeting interventions.
2024-04-29 | Interferon-gamma contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome.
Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi-system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the Ndufs4(-/-) mouse model of LS: treatment of Ndufs4(-/-) mice with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon-gamma (IFNγ) and interferon gamma-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS. To establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout animals, as well as IFNγ and IP10 heterozygous, Ndufs4(-/-)/Ifng(+/-) and Ndufs4(-/-)/IP10(+/-), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS. Loss of IP10 does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage-dependent manner, though the benefits are modest compared to Csf1r inhibition. IFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.
2023-07-10 | IFNγ modestly contributes to disease progression in theNdufs4(-/-) model of Leigh syndrome while IP10 is dispensable
Abstract Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disease characterized by severe neurologic and metabolic abnormalities. The defining feature of the disease is the presence of symmetric, bilateral, progressive necrotizing lesions in the brain stem, cerebellum, and basal ganglia. The pathogenic mechanisms underlying disease initiation and progression in LS have yet to be elucidated. Recent evidence demonstrates that the immune system plays a key role in LS pathogenesis. Treatment with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease in the Ndufs4 (-/-) mouse model of LS, but the mechanisms leading to immune activation and governing disease progression remain to be elucidated. In recent work, the cytokines IFNγ and IFNγ-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4 (-/-) brainstem. Given their role as macrophage-activating factors, here we sought to assess the role of IFNγ and IP10 in LS using by generating Ndufs4 (-/-)/ Ifng (-/-) and Ndufs4 (-/-)/ IP10 (-/-) double knockout lines. We find that IP10 alone does not significantly impact the onset or progression of disease in the Ndufs4 (-/-) model, while IFNγ loss significantly, but modestly, improves survival. These data indicate that IFNγ contributes to pathology, but that IFNγ and IP10 are both dispensable for overall disease course of LS. Our findings support some role for IFNγ targeting therapies in the management of mitochondrial disease, but suggest they may provide only modest benefits, at least in LS.
2023-02-03 | PET117 Modulates Mitochondrial-encoded COX1 Translation by stabilizing TACO1
Abstract Mitochondria are the most important organelles in energy metabolism. Complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are formed by proteins of dual origin synthesized in the cytosol or mitochondria. The mechanisms underlying specific translation by mitoribosomes in mammals are largely unknown. Here, we report a chaperone protein of cytochrome c oxidase (COX) assembly, PET117 plays a critical role in the synthesis of mitochondrial-encoded COX1 protein in human cells. Lack of PET117 impaired mitochondrial function via suppression of mitochondrial oxygen consumption rate (OCR), probably due to reduced stability of TACO1, a COX1 translational activator. We uncovered the role of PET117 in mitochondrial regulation and a novel PET117-TACO1 axis modulating mitochondrial gene expression.
2022-09-08 | The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.
Genetic mitochondrial diseases represent a significant challenge to human health. These diseases are extraordinarily heterogeneous in clinical presentation and genetic origin, and often involve multi-system disease with severe progressive symptoms. Mitochondrial diseases represent the most common cause of inherited metabolic disorders and one of the most common causes of inherited neurologic diseases, yet no proven therapeutic strategies yet exist. The basic cell and molecular mechanisms underlying the pathogenesis of mitochondrial diseases have not been resolved, hampering efforts to develop therapeutic agents. In recent pre-clinical work, we have shown that pharmacologic agents targeting the immune system can prevent disease in the Ndufs4(KO) model of Leigh syndrome, indicating that the immune system plays a causal role in the pathogenesis of at least this form of mitochondrial disease. Intriguingly, a number of case reports have indicated that immune-targeting therapeutics may be beneficial in the setting of genetic mitochondrial disease. Here, we summarize clinical and pre-clinical evidence suggesting a key role for the immune system in mediating the pathogenesis of at least some forms of genetic mitochondrial disease. Significant clinical and pre-clinical evidence indicates a key role for the immune system as a significant in the pathogenesis of at least some forms of genetic mitochondrial disease.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
10 orphan drug designations for Leigh syndrome.
10 orphan drug designations for Leigh syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated virus 9 human NADH:ubiquinone oxidoreductase subunit S4 | gene therapies | FDA | 2024-10-22 | — | National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) |
2-((hydroxy((R)-2-(((5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl)oxy)-3-(((E)-octadec-2-en-1-yl)oxy)propoxy)phosphoryl)oxy)ethan-1-ammonium | small molecules | FDA | 2024-09-26 | — | Institute of Rheological Functions of Food |
Methyl 4-(2-acetamidoethylsulfanyl)-4-oxobutanoate | small molecules | EMA | 2023-12-13 | — | Pharming Technologies B.V. |
Sildenafil citrate | small molecules | EMA | 2023-10-13 | — | Charite Universitaetsmedizin Berlin KöR |
Cannabidiol | small molecules | EMA | 2023-07-25 | — | Universitat Autònoma De Barcelona |
Adeno-associated viral vector serotype 9 containing the human SURF1 gene | gene therapies | EMA | 2021-11-12 | — | Raremoon Consulting Esp S.L. |
TGTX-102, an adeno-associated virus serotype 9 (AAV9) vector with engineered transgene encoding the human SURF1 protein. | gene therapies | FDA | 2020-10-20 | — | University of Texas Southwestern Medical Center |
Sonlicromanol hydrochloride [KH-176] | small molecules | EMA | 2014-10-15 | — | Khondrion B.V. |
vatiquinone | small molecules | FDA | 2014-06-04 | — | PTC Therapeutics, Inc. |
Vatiquinone | small molecules | EMA | 2011-12-09 | — | PTC Therapeutics International Limited |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.