RARE DISEASE
Mitochondrial disease
Mitochondrial disease
Mitochondrial disease
Drug discovery
5
drugs
With orphan designations
Overview
Mitochondrial diseases are inherited disorders of oxidative phosphorylation caused by mutations in nuclear or mitochondrial DNA, leading to cellular energy deficits. They manifest with multisystem involvement, predominantly affecting high-energy-demand organs (brain, heart, muscles) and presenting with symptoms ranging from myopathy to metabolic strokes, seizures, and organ failure [1][5][9].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
3,121 drug discovery papers about Mitochondrial disease, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,121 drug discovery papers about Mitochondrial disease, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | A case of severe enteritis following CapeOX therapy in a postoperative rectal cancer patient with m.3243A>G-associated mitochondrial disease.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder characterized by impaired oxidative phosphorylation and reduced ATP production, resulting in increased organ vulnerability to metabolic stress. Fluoropyrimidine agents, such as 5-fluorouracil (5-FU), are widely used to treat colorectal cancer and can induce gastrointestinal toxicity not only through inhibition of thymidylate synthase and suppression of nucleic acid synthesis but also via RNA misincorporation, translational defects, and mitochondrial dysfunction in intestinal epithelial cells. The coexistence of metabolic vulnerability associated with m.3243A>G-related mitochondrial dysfunction and drug-induced mitochondrial injury may synergistically exacerbate intestinal toxicity, potentially leading to severe enteritis. A 40-year-old woman with m.3243A>G-associated mitochondrial disease within the MELAS spectrum underwent radical resection for perforated rectal cancer with synchronous liver metastases. Her postoperative course was uneventful, and she was discharged without complications. CapeOX therapy (capecitabine plus oxaliplatin) was initiated as adjuvant chemotherapy. Ten days after the start of the third cycle, she developed intermittent fever, abdominal distension, and diarrhea. Computed tomography revealed diffuse edema throughout the small intestine with massive ascites. Malignant peritonitis was considered unlikely based on imaging, ascites analysis, and cytology, whereas infectious enteritis was not strongly suspected based on the clinical course. Chemotherapy-induced enteritis associated with CapeOX was therefore strongly suspected, and the regimen was discontinued. The gastrointestinal symptoms improved, and tumor marker levels normalized. This case suggests that underlying mitochondrial dysfunction may enhance fluoropyrimidine-related intestinal toxicity, indicating that careful risk assessment and close monitoring are required when administering chemotherapy to patients with underlying mitochondrial disorders.
2026-09-16 | MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2 A > G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete β-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodeling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype, linking metabolic rewiring to ECM homeostasis. Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.
2026-09-10 | Progress on Mechanisms of Therapeutic Potential of Oxygen Delivery in Brain Disorders.
Oxygen is both essential and potentially toxic to the brain, which consumes 20-25% of the body's resting metabolic rate despite comprising only 2% of total body weight. The exquisite sensitivity of neural tissue to oxygen imbalance positions oxygen delivery as a critical determinant of both pathophysiology and therapeutic opportunity in brain disorders. This review synthesizes recent advances in our understanding of how oxygen sensing and delivery can be harnessed for therapeutic benefit across the spectrum of neurological conditions. We examine the molecular machinery of oxygen sensing, including the canonical PHD-HIF-pVHL pathway as well as newly identified oxygen sensors such as Jumonji C domain histone demethylases and cysteine dioxygenase. We then explore how perturbations in oxygen delivery contribute to neurodegenerative diseases, stroke, traumatic brain injury, and neurodevelopmental disorders. Emerging therapeutic strategies are critically evaluated, including normobaric and hyperbaric oxygen therapy, therapeutic acute intermittent hypoxia, hypoxia preconditioning, and pharmacological targeting of oxygen-sensing pathways. Moreover, the emerging concept of tissue-specific oxygen "set points" suggests that both hypoxia and hyperoxia can be pathological, and that restoring optimal oxygenation-rather than simply maximizing oxygen delivery-may represent a more nuanced therapeutic approach. Notably, recent preclinical evidence demonstrating that hypoxia itself can reverse pathology in mitochondrial disease models challenges conventional assumptions and opens new avenues for treating brain disorders characterized by relative hyperoxia. Understanding the mechanisms by which oxygen delivery influences neuroinflammation, mitochondrial function, and neural plasticity will be essential for translating these insights into effective clinical interventions.
2026-09-09 | Coenzyme Q10 supplementation restores mitochondrial respiration in patients with primary CoQ10 deficiency caused by novel COQ2 and COQ4 variants.
Primary coenzyme Q10 deficiencies (COQ10D) are rare mitochondrial disorders caused by pathogenic variants in genes involved in coenzyme Q10 (CoQ10) biosynthesis, leading to impaired mitochondrial respiration and heterogeneous neurological phenotypes. In this study, we identified and functionally characterized novel recessive variants in COQ2 and COQ4 using whole-exome sequencing. One proband carried a homozygous COQ2 variant (c.1039 A > G; p.Ser347Gly), while the second harbored compound heterozygous COQ4 variants (c.238 C > T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7). Variant segregation was confirmed by Sanger sequencing, and in silico protein modelling predicted deleterious structural effects. Mitochondrial function was assessed in freshly isolated platelets from probands, family members, and healthy controls using high-resolution respirometry. The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation, whereas the COQ4 proband, already receiving CoQ10, showed near-normal mitochondrial function. Following three months of CoQ10 supplementation, the COQ2 proband showed significant improvement in ATP synthesis and reduced proton leak, accompanied by clinical neurological improvement. mRNA expression analysis revealed feedback regulation, while protein levels of ETC complexes I-V remained unchanged. Importantly, CoQ10 supplementation in healthy individuals did not alter mitochondrial respiration, confirming the specificity of therapeutic benefit in COQ10Ds. Overall, in addition to expanding the genetic spectrum of COQ10Ds, this study also provides functional evidence that defective mitochondrial function in these conditions is, at least in part, reversible with targeted CoQ10 therapy, underscoring the importance of early genetic diagnosis and timely initiation of CoQ10 supplementation.
2026-09-08 | Endothelial-mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction.
Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline). Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception-October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (k mono , DP/k mono ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale. Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs. Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.
gene therapies
2026-09-08 | Allotopic Expression of ND6 Restores Vision in a Mitochondrial Disease Model.
Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nuclear-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, We compared the therapeutic efficacy in mutant mice at different ages and pre-symptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provide critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.
2026-08-31 | A multisystemic mitochondrial disease caused by the MT-TD variant m.7520G>A
A multisystemic mitochondrial disease caused by the MT-TD variant m.7520G>A
2026-07-28 | CARE checklist for 'Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease.'
Completed CARE checklist for 'Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease.'
2026-07-21 | TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management. To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes. We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease. The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes. TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
2026-06-26 | Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
Mitochondrial DNA (mtDNA) mutations are associated with a diverse spectrum of diseases and pose a significant threat to human health. Despite their importance as therapeutic targets, the unique structural and electrochemical properties of mitochondria-most notably the impermeable inner mitochondrial membrane and the high membrane potential-present formidable challenges for the targeted delivery of therapeutic agents. Currently, there are no approved curative treatments for patients harboring pathogenic mtDNA mutations. In this review, we discuss recent advancements in gene therapy for mitochondrial genome-related disorders, with a particular focus on allotopic expression of mtDNA-encoded genes and mitochondrial genome editing technologies. We conclude that allotopic expression currently stands as the most promising approach for near-term clinical implementation. But we also pay great attention to programmable nucleases and base editors utilizing RNA-independent DNA recognition which are evolving with remarkable speed.
proteins
2026-08-01 | Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma.
Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical ndufs2 -/- C. elegans model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and C. elegans models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells' survival, as well as mitochondrial stress in SLC25A46 -/- C. elegans . Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.
2026-07-01 | Unusual Variants in NDUFAF6-Associated Mitochondrial Disease
A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6 , i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768 T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.
2026-06-29 | A de novo TWNK Variant Mimicked Sporadic Chronic Progressive External Ophthalmoplegia.
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis, external ophthalmoplegia, and proximal muscle weakness without any relevant family history. A muscle biopsy supported the diagnosis of sporadic CPEO. However, a muscle DNA analysis revealed multiple mitochondrial DNA (mtDNA) deletions. Whole-exome sequencing identified a heterozygous pathogenic TWNK variant [c.1121G>A (p.Arg374Gln)] absent in her parents, suggesting a de novo origin. Although TWNK pathogenic variants typically cause autosomal dominant CPEO, this case mimicked a sporadic form, thus highlighting the importance of a nuclear gene analysis in such cases.
2026-05-04 | Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.
Mitochondrial diseases are rare multisystem disorders caused by pathogenic variants in mitochondrial or nuclear DNA. We report a 23-year-old male presenting with exercise intolerance, fatigue, sluggish responsiveness, and a history of ptosis and bilateral hearing loss. Echocardiography revealed left ventricular hypertrophy, while brain MRI showed cerebellar atrophy and ventricular enlargement. Laboratory tests demonstrated elevated serum lactate, HbA1c, and high-sensitivity cardiac troponin T. Targeted sequencing identified a pathogenic m.3243A > G variant in the MT-TL1 gene with 55.6% heteroplasmy, confirming mitochondrial encephalomyopathy with cardiac involvement. This case highlights the phenotypic heterogeneity and diagnostic challenges of m.3243A > G-related disorders.
2026-03-17 | Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP. We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38. Next-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing. These cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.
cell therapies
2026-09-15 | Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
2026-09-02 | Pronuclear Transfer and Maternal Spindle Transfer in the Mouse.
Maternal Spindle Transfer (MST) and Pronuclear Transfer (PNT) are micromanipulation techniques that allow the transfer of the nuclear material from one oocyte or zygote to the cytoplasm of another. The application of these techniques has provided novel insights into nuclear-cytoplasmic interactions necessary for development, as well as fundamental discoveries such as genomic imprinting. Now, after extensive pre-clinical research, PNT and MST are starting to be used clinically for Mitochondrial Donation (also known as mitochondrial replacement therapy) and for patients with a history of repeated IVF failure. Here, we describe the methods for PNT and MST currently used in the mouse model. The techniques are readily adaptable for application to other mammalian species, including humans.
2026-08-19 | The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized. A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction. We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026. Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs. This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI. N/A.
2026-06-04 | Mitochondrial donation and human reproduction: Clinical, ethical and legal aspects.
Women carriers of a disease caused by changes in mitochondrial DNA (mtDNA) seeking to achieve motherhood, currently have three options: (i) prenatal testing, via CVS or amniocentesis for women aiming to conceive naturally and test the health of the fetus during development; (ii) preimplantation genetic testing (PGT), which allows for the selection of embryos without mtDNA mutations or with the lowest possible chance of pathogenic mtDNA presence, and (iii) egg donation. The United Kingdom and Australia have approved two methods for replacing mutant mtDNA: maternal spindle transfer (MST) and pronuclear transfer (PNT). In MST, the maternal nuclear DNA is transferred from the patient's oocyte into an enucleated donor oocyte from which the maternal spindle has been removed. The reconstituted egg would then be fertilized by the intended father's sperm and the newly formed embryo implanted in the intended mother. In PNT, first mother's eggs are fertilized using the intended father's sperm, then the pronuclei of the embryo are transferred to a recipient embryo, from which the pronuclei have been removed. This paper will illustrate the basis of mtDNA-related diseases and the approaches to minimize transmission to offspring. Then, it will focus on the main ethical and legal/regulatory complexities as to various types of nuclear transfer to prevent mtDNA diseases, the risks to the child and future generations, and the issues related to germline changing. Our conclusion is that the two main methods developed to replace pathogenic mtDNA variants are morally approvable because they afford the newborn child quality of life.
2026-05-23 | Mitoredox shifts in mitochondrial dysfunction.
Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.
other
2026-07-25 | Immune Modulatory Therapy for Severe Dengue Hemorrhagic Fever in a Patient With Mitochondrial Complex I Deficiency: A Case Report.
Dengue virus (DENV) poses a serious global health challenge, particularly in cases of dengue hemorrhagic fever (DHF). Patients with preexisting mitochondrial disorders may be at increased risk for complications due to the specific impact of DENV on mitochondrial-dependent cellular processes and immune function. We describe a 16-year-old male with known mitochondrial complex I deficiency caused by a homozygous likely pathogenic variant in NDUFV1 who subsequently developed DHF. His illness was marked by rapidly worsening weakness, respiratory distress, intracranial hemorrhage, and seizures. His clinical course was further complicated by encephalitis, arachnoiditis, and myelitis requiring extensive immunomodulation. He received corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (PLEX), which led to improvement and partial recovery of functional status. This case highlights several rare complications of dengue fever, the impact of DENV on mitochondrial function, and underscores the complexity of managing infectious diseases in individuals with underlying mitochondrial disorders.
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.
2025-12-01 | Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.
2025-06-25 | Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.
We present a general method for in-cellulo delivery of 2'-O-methyl (2'-OMe) RNA oligonucleotides (oligos) to mitochondria for antisense applications, with potential for implementation in other mitochondrial DNA (mtDNA)-targeted therapies. Exosomes, which are nanoscale, naturally occurring extracellular vesicles (EVs), have been employed for biotechnology applications in oligonucleotide delivery in recent years. We discovered that exosomes from fetal bovine serum (FBS) can be used as a simple and biologically compatible delivery agent of 2'-OMe RNA antisense oligonucleotides to cellular mitochondria, leading to target protein knockdown. While most RNA interference and antisense mechanisms occur in the cytoplasm or nucleus, the need for mitochondrial targeting has become increasingly apparent. Mitochondrial disease describes a variety of currently incurable syndromes that especially affect organs requiring significant energy including the muscles, heart, and brain. Many of these syndromes result from mutations in mtDNA, which codes for the 13 proteins of the oxidative phosphorylation system and are thus often implicated in inherited metabolic disorders.
2025-03-21 | Chromogen-based double immunohistochemical detection of mitochondrial respiratory chain deficiencies in human brain tissue.
Studies of the mitochondrial respiratory chain (MRC) have given important insights into the pathology of mitochondrial and neurodegenerative disorders. Immunohistochemical methods for staining MRC complexes are particularly valuable for assessing quantitative changes in situ, especially in complex tissues with cellular heterogeneity, such as the brain. However, traditional approaches have notable limitations. Chromogen-based staining, while preserving tissue morphology, has been restricted to a single antigen per section, preventing co-assessment of MRC complexes and mitochondrial mass on the same section. Immunofluorescence, which allows multiplex staining of multiple targets, partially addresses this limitation but compromises tissue morphology and can be highly variable in postmortem brain samples. To address these challenges, we have established a dual-antigen, chromogen-based immunohistochemical method that allows simultaneous assessment of each MRC complex and the mitochondrial marker voltage-dependent anion channel 1 (VDAC1) on the same section. As proof of concept, we apply this method on brain tissue from patients with neurological disease caused by mutations in the mitochondrial DNA polymerase gamma (POLG). Our findings demonstrate that this approach is both reliable and robust. Moreover, this method enables more precise identification of MRC deficiencies in neurons and significantly reduces the amount of tissue required for analysis, a critical advantage when working with scarce human brain samples.
small molecules
2026-09-24 | A case of severe enteritis following CapeOX therapy in a postoperative rectal cancer patient with m.3243A>G-associated mitochondrial disease.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder characterized by impaired oxidative phosphorylation and reduced ATP production, resulting in increased organ vulnerability to metabolic stress. Fluoropyrimidine agents, such as 5-fluorouracil (5-FU), are widely used to treat colorectal cancer and can induce gastrointestinal toxicity not only through inhibition of thymidylate synthase and suppression of nucleic acid synthesis but also via RNA misincorporation, translational defects, and mitochondrial dysfunction in intestinal epithelial cells. The coexistence of metabolic vulnerability associated with m.3243A>G-related mitochondrial dysfunction and drug-induced mitochondrial injury may synergistically exacerbate intestinal toxicity, potentially leading to severe enteritis. A 40-year-old woman with m.3243A>G-associated mitochondrial disease within the MELAS spectrum underwent radical resection for perforated rectal cancer with synchronous liver metastases. Her postoperative course was uneventful, and she was discharged without complications. CapeOX therapy (capecitabine plus oxaliplatin) was initiated as adjuvant chemotherapy. Ten days after the start of the third cycle, she developed intermittent fever, abdominal distension, and diarrhea. Computed tomography revealed diffuse edema throughout the small intestine with massive ascites. Malignant peritonitis was considered unlikely based on imaging, ascites analysis, and cytology, whereas infectious enteritis was not strongly suspected based on the clinical course. Chemotherapy-induced enteritis associated with CapeOX was therefore strongly suspected, and the regimen was discontinued. The gastrointestinal symptoms improved, and tumor marker levels normalized. This case suggests that underlying mitochondrial dysfunction may enhance fluoropyrimidine-related intestinal toxicity, indicating that careful risk assessment and close monitoring are required when administering chemotherapy to patients with underlying mitochondrial disorders.
2026-09-16 | MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease.
Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2 A > G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover, accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete β-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodeling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype, linking metabolic rewiring to ECM homeostasis. Overall, this clinically relevant model uncovers how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.
2026-09-10 | Progress on Mechanisms of Therapeutic Potential of Oxygen Delivery in Brain Disorders.
Oxygen is both essential and potentially toxic to the brain, which consumes 20-25% of the body's resting metabolic rate despite comprising only 2% of total body weight. The exquisite sensitivity of neural tissue to oxygen imbalance positions oxygen delivery as a critical determinant of both pathophysiology and therapeutic opportunity in brain disorders. This review synthesizes recent advances in our understanding of how oxygen sensing and delivery can be harnessed for therapeutic benefit across the spectrum of neurological conditions. We examine the molecular machinery of oxygen sensing, including the canonical PHD-HIF-pVHL pathway as well as newly identified oxygen sensors such as Jumonji C domain histone demethylases and cysteine dioxygenase. We then explore how perturbations in oxygen delivery contribute to neurodegenerative diseases, stroke, traumatic brain injury, and neurodevelopmental disorders. Emerging therapeutic strategies are critically evaluated, including normobaric and hyperbaric oxygen therapy, therapeutic acute intermittent hypoxia, hypoxia preconditioning, and pharmacological targeting of oxygen-sensing pathways. Moreover, the emerging concept of tissue-specific oxygen "set points" suggests that both hypoxia and hyperoxia can be pathological, and that restoring optimal oxygenation-rather than simply maximizing oxygen delivery-may represent a more nuanced therapeutic approach. Notably, recent preclinical evidence demonstrating that hypoxia itself can reverse pathology in mitochondrial disease models challenges conventional assumptions and opens new avenues for treating brain disorders characterized by relative hyperoxia. Understanding the mechanisms by which oxygen delivery influences neuroinflammation, mitochondrial function, and neural plasticity will be essential for translating these insights into effective clinical interventions.
2026-09-09 | Coenzyme Q10 supplementation restores mitochondrial respiration in patients with primary CoQ10 deficiency caused by novel COQ2 and COQ4 variants.
Primary coenzyme Q10 deficiencies (COQ10D) are rare mitochondrial disorders caused by pathogenic variants in genes involved in coenzyme Q10 (CoQ10) biosynthesis, leading to impaired mitochondrial respiration and heterogeneous neurological phenotypes. In this study, we identified and functionally characterized novel recessive variants in COQ2 and COQ4 using whole-exome sequencing. One proband carried a homozygous COQ2 variant (c.1039 A > G; p.Ser347Gly), while the second harbored compound heterozygous COQ4 variants (c.238 C > T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7). Variant segregation was confirmed by Sanger sequencing, and in silico protein modelling predicted deleterious structural effects. Mitochondrial function was assessed in freshly isolated platelets from probands, family members, and healthy controls using high-resolution respirometry. The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation, whereas the COQ4 proband, already receiving CoQ10, showed near-normal mitochondrial function. Following three months of CoQ10 supplementation, the COQ2 proband showed significant improvement in ATP synthesis and reduced proton leak, accompanied by clinical neurological improvement. mRNA expression analysis revealed feedback regulation, while protein levels of ETC complexes I-V remained unchanged. Importantly, CoQ10 supplementation in healthy individuals did not alter mitochondrial respiration, confirming the specificity of therapeutic benefit in COQ10Ds. Overall, in addition to expanding the genetic spectrum of COQ10Ds, this study also provides functional evidence that defective mitochondrial function in these conditions is, at least in part, reversible with targeted CoQ10 therapy, underscoring the importance of early genetic diagnosis and timely initiation of CoQ10 supplementation.
2026-09-08 | Endothelial-mitochondrial coupling in mitochondrial disease: A systematic review and quantitative synthesis of vascular, biochemical, and oxidative bioenergetic dysfunction.
Mitochondrial diseases are multisystem disorders in which defects in oxidative phosphorylation disrupt cellular bioenergetics and redox signaling across the vasculature and heart. Because mitochondrial function is closely linked to endothelial nitric oxide (NO) production, we hypothesized that mitochondrial diseases manifest as a NO-deficiency endotheliopathy affecting conduit and microvascular function. To evaluate this, we performed a systematic review with quantitative synthesis of human studies reporting vascular reactivity, biochemical NO production, or myocardial metabolic imaging, aiming to define the magnitude of impairment and responsiveness to NO-precursor therapy (l-arginine or l-citrulline). Following PRISMA 2020 guidelines, we conducted a comprehensive search (inception-October 2025) identifying clinical studies of genetically or clinically confirmed mitochondrial disease with quantitative endothelial or bioenergetic endpoints. Eligible measures included flow-mediated dilation (FMD), reactive hyperemia index (RHI), passive-leg-movement (PLM) hyperemia, absolute synthesis rate of NO metabolites (ASR NOm), and positron emission tomography (PET)-derived myocardial oxidative indices (k mono , DP/k mono ). Quantitative synthesis used Hedges g for between-group comparisons and standardized mean change (SMC) for within-subject responses. Risk of bias was evaluated using ROBINS-I and a modified Newcastle-Ottawa Scale. Seven studies met these inclusion criteria, comprising 76 mitochondrial-disease subjects and 81 controls (ages 8-63 years). Across all vascular and metabolic domains, mitochondrial disease was associated with marked endothelial and bioenergetic impairment. Macro- and microvascular dysfunction, reflected by reduced FMD, RHI, and PLM hyperemia, demonstrated severe endothelium-specific abnormalities. Biochemical assays showed diminished NO synthesis. Myocardial PET imaging revealed reduced oxidative rate constants and increased energetic inefficiency despite preserved perfusion. Nitric oxide synthesis-precursor therapy was associated with improved endothelial reactivity (increased FMD, RHI, and ASR NOm) and significant, modest improvements in myocardial oxidative metabolism, consistent with partial restoration of endothelial NO signaling. Effect sizes collectively supported a reversible NO-deficiency endotheliopathy. The risk-of-bias assessment indicated moderate-to-good methodological quality, with limitations primarily related to small sample sizes and nonrandomized designs. Mitochondrial disease is characterized by significant impairments in vascular reactivity, NO signaling, and myocardial bioenergetics. Improvements in endothelial function and NO synthesis following l-arginine or l-citrulline supplementation are consistent with a role for impaired endothelial NO signaling in the vascular manifestations of mitochondrial disease. These findings highlight the vascular endothelium as a potential therapeutic target and underscore the need for future clinical intervention trials that use standardized vascular and bioenergetic endpoints.
gene therapies
2026-09-08 | Allotopic Expression of ND6 Restores Vision in a Mitochondrial Disease Model.
Mutations in mitochondrial DNA (mtDNA) cause various mitochondrial diseases that are currently incurable. Allotopic expression of nuclear-recoded mitochondrial genes represents a promising therapeutic strategy, given its demonstrated capacity to restore mitochondrial function in human cell models harboring mtDNA mutations. However, the in vivo evaluation of allotopic gene therapy has been hindered by optimization challenges and the lack of appropriate animal models. Here, we overcome these limitations by utilizing an optimized AAV2-ND6 construct with codon optimization and mitochondrial targeting sequence in a mouse model bearing the homoplasmic ND6P25L mutation, which recapitulates Leber hereditary optic neuropathy (LHON). High-dose administration of the AAV2-ND6 construct resulted in robust, sustained expression within the retina and optic nerve without apparent systemic toxicity. Strikingly, We compared the therapeutic efficacy in mutant mice at different ages and pre-symptomatic intervention with AAV2-ND6 effectively attenuated disease progression, mitigated retinal cellular deficiencies and optic nerve damage, and restored visual function in ND6P25L mice. Mechanistically, allotopic ND6 expression markedly rescued the mitochondrial dysfunction, corrected dysregulated retinol metabolism and phototransduction pathways, and suppressed apoptotic processes in the mutant retina. Our study validates the safety and therapeutic potential of allotopic expression in vivo and provide critical mechanistic insights into its role in treating LHON and other mitochondrial diseases.
2026-08-31 | A multisystemic mitochondrial disease caused by the MT-TD variant m.7520G>A
A multisystemic mitochondrial disease caused by the MT-TD variant m.7520G>A
2026-07-28 | CARE checklist for 'Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease.'
Completed CARE checklist for 'Re-investigating recurrent Refractory Status Epilepticus revealed POLG-Related Mitochondrial Disease.'
2026-07-21 | TTC19-related mitochondrial disease: A characteristic neuroimaging signature?
TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management. To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes. We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease. The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes. TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
2026-06-26 | Gene Therapy Tools for Diseases Caused by Mutations of the Mitochondrial Genome.
Mitochondrial DNA (mtDNA) mutations are associated with a diverse spectrum of diseases and pose a significant threat to human health. Despite their importance as therapeutic targets, the unique structural and electrochemical properties of mitochondria-most notably the impermeable inner mitochondrial membrane and the high membrane potential-present formidable challenges for the targeted delivery of therapeutic agents. Currently, there are no approved curative treatments for patients harboring pathogenic mtDNA mutations. In this review, we discuss recent advancements in gene therapy for mitochondrial genome-related disorders, with a particular focus on allotopic expression of mtDNA-encoded genes and mitochondrial genome editing technologies. We conclude that allotopic expression currently stands as the most promising approach for near-term clinical implementation. But we also pay great attention to programmable nucleases and base editors utilizing RNA-independent DNA recognition which are evolving with remarkable speed.
proteins
2026-08-01 | Targeted modulation of IGFBP5/IGF1, THPO, and P38 MAPK signaling are potent therapeutic strategies generalizable for mitochondrial respiratory chain disease and osteosarcoma.
Primary mitochondrial diseases (PMD) have limited disease-modifying therapies, currently applicable to only 3 of over 400 discrete gene disorders. Cycloheximide (CHX) is a global cytosolic translation inhibitor we previously reported to rescue PMD preclinical models, although its toxicity precluded clinical development. To identify specific mediators underlying CHX treatment benefit in PMD, SOMAscan-based proteomics was performed in complex I deficient and genetic disease fibroblast cell line models grown in galactose. Thrombopoietin (THPO) and insulin-like growth factor binding protein 5 (IGFBP5) were the only two differentially regulated proteins, together with ERK/MAPK pathway dysregulation, identified upon CHX treatment in PMD versus healthy control cells. THPO inhibition by siRNA or pharmacologic approaches rescued stress-induced viability loss in patient fibroblasts having diverse PMD gene etiologies, and significantly improved mitochondrial stress, linear growth, and neuromuscular function in a classical ndufs2 -/- C. elegans model. IGFBP5 overexpression by lentiviral or mRNA approaches rescued cell viability across distinct PMD gene etiologies, as did IGF1 pharmacologic inhibition across both PMD mutant and C. elegans models. MAPK pharmacologic inhibition rescued multiple distinct complex I disease cells' survival, as well as mitochondrial stress in SLC25A46 -/- C. elegans . Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models. Additionally, single or combined pharmacologic inhibition of THPO or IGF1 significantly enhanced primary and metastatic osteosarcoma cell death. Collectively, targeted small molecule and genetic modulation of THPO, IGF1, or MAPK recapitulated the significant therapeutic benefit of CHX in PMD, while avoiding global translation inhibition. These novel PMD therapies likely confer benefit by attenuating MAPK-driven autophagy and potentially promoting noncanonical glucose uptake, improving cellular energy balance. Overall, these glucose signaling cellular pathway targets hold broad therapeutic promise for PMD patients, warranting further clinical research development.
2026-07-01 | Unusual Variants in NDUFAF6-Associated Mitochondrial Disease
A 6-year-old female with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction was evaluated in the National Institutes of Health Undiagnosed Diseases Program. Although exome sequencing did not yield a diagnosis, family genome sequencing revealed biallelic variants in NDUFAF6 , i.e., a paternally inherited intronic variant (NM_152416.3:c.298-768 T>C) and a maternally inherited 1.6 kb deletion (NC_000008.11:g.95044573_95046180del, spanning exon 5). NDUFAF6 plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDUFS8. Variants in NDUFAF6 are associated with two OMIM disorders i.e., Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotypes include proximal tubule dysfunction and degeneration of the central nervous system. The intronic single nucleotide variant in this case (sometimes referred to as the Acadian variant) has been reported to cause aberrant splicing. This case highlights the need to consider comprehensive sequencing methods, such as genome sequencing, to identify atypical variants in planning a comprehensive diagnostic strategy.
2026-06-29 | A de novo TWNK Variant Mimicked Sporadic Chronic Progressive External Ophthalmoplegia.
Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis, external ophthalmoplegia, and proximal muscle weakness without any relevant family history. A muscle biopsy supported the diagnosis of sporadic CPEO. However, a muscle DNA analysis revealed multiple mitochondrial DNA (mtDNA) deletions. Whole-exome sequencing identified a heterozygous pathogenic TWNK variant [c.1121G>A (p.Arg374Gln)] absent in her parents, suggesting a de novo origin. Although TWNK pathogenic variants typically cause autosomal dominant CPEO, this case mimicked a sporadic form, thus highlighting the importance of a nuclear gene analysis in such cases.
2026-05-04 | Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.
Mitochondrial diseases are rare multisystem disorders caused by pathogenic variants in mitochondrial or nuclear DNA. We report a 23-year-old male presenting with exercise intolerance, fatigue, sluggish responsiveness, and a history of ptosis and bilateral hearing loss. Echocardiography revealed left ventricular hypertrophy, while brain MRI showed cerebellar atrophy and ventricular enlargement. Laboratory tests demonstrated elevated serum lactate, HbA1c, and high-sensitivity cardiac troponin T. Targeted sequencing identified a pathogenic m.3243A > G variant in the MT-TL1 gene with 55.6% heteroplasmy, confirming mitochondrial encephalomyopathy with cardiac involvement. This case highlights the phenotypic heterogeneity and diagnostic challenges of m.3243A > G-related disorders.
2026-03-17 | Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP. We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38. Next-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing. These cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.
cell therapies
2026-09-15 | Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease.
Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.
2026-09-02 | Pronuclear Transfer and Maternal Spindle Transfer in the Mouse.
Maternal Spindle Transfer (MST) and Pronuclear Transfer (PNT) are micromanipulation techniques that allow the transfer of the nuclear material from one oocyte or zygote to the cytoplasm of another. The application of these techniques has provided novel insights into nuclear-cytoplasmic interactions necessary for development, as well as fundamental discoveries such as genomic imprinting. Now, after extensive pre-clinical research, PNT and MST are starting to be used clinically for Mitochondrial Donation (also known as mitochondrial replacement therapy) and for patients with a history of repeated IVF failure. Here, we describe the methods for PNT and MST currently used in the mouse model. The techniques are readily adaptable for application to other mammalian species, including humans.
2026-08-19 | The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized. A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction. We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026. Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs. This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI. N/A.
2026-06-04 | Mitochondrial donation and human reproduction: Clinical, ethical and legal aspects.
Women carriers of a disease caused by changes in mitochondrial DNA (mtDNA) seeking to achieve motherhood, currently have three options: (i) prenatal testing, via CVS or amniocentesis for women aiming to conceive naturally and test the health of the fetus during development; (ii) preimplantation genetic testing (PGT), which allows for the selection of embryos without mtDNA mutations or with the lowest possible chance of pathogenic mtDNA presence, and (iii) egg donation. The United Kingdom and Australia have approved two methods for replacing mutant mtDNA: maternal spindle transfer (MST) and pronuclear transfer (PNT). In MST, the maternal nuclear DNA is transferred from the patient's oocyte into an enucleated donor oocyte from which the maternal spindle has been removed. The reconstituted egg would then be fertilized by the intended father's sperm and the newly formed embryo implanted in the intended mother. In PNT, first mother's eggs are fertilized using the intended father's sperm, then the pronuclei of the embryo are transferred to a recipient embryo, from which the pronuclei have been removed. This paper will illustrate the basis of mtDNA-related diseases and the approaches to minimize transmission to offspring. Then, it will focus on the main ethical and legal/regulatory complexities as to various types of nuclear transfer to prevent mtDNA diseases, the risks to the child and future generations, and the issues related to germline changing. Our conclusion is that the two main methods developed to replace pathogenic mtDNA variants are morally approvable because they afford the newborn child quality of life.
2026-05-23 | Mitoredox shifts in mitochondrial dysfunction.
Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.
other
2026-07-25 | Immune Modulatory Therapy for Severe Dengue Hemorrhagic Fever in a Patient With Mitochondrial Complex I Deficiency: A Case Report.
Dengue virus (DENV) poses a serious global health challenge, particularly in cases of dengue hemorrhagic fever (DHF). Patients with preexisting mitochondrial disorders may be at increased risk for complications due to the specific impact of DENV on mitochondrial-dependent cellular processes and immune function. We describe a 16-year-old male with known mitochondrial complex I deficiency caused by a homozygous likely pathogenic variant in NDUFV1 who subsequently developed DHF. His illness was marked by rapidly worsening weakness, respiratory distress, intracranial hemorrhage, and seizures. His clinical course was further complicated by encephalitis, arachnoiditis, and myelitis requiring extensive immunomodulation. He received corticosteroids, intravenous immunoglobulin (IVIG), and plasma exchange (PLEX), which led to improvement and partial recovery of functional status. This case highlights several rare complications of dengue fever, the impact of DENV on mitochondrial function, and underscores the complexity of managing infectious diseases in individuals with underlying mitochondrial disorders.
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.
2025-12-01 | Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.
2025-06-25 | Exosome-Mediated Mitochondrial Delivery of Antisense Oligonucleotides.
We present a general method for in-cellulo delivery of 2'-O-methyl (2'-OMe) RNA oligonucleotides (oligos) to mitochondria for antisense applications, with potential for implementation in other mitochondrial DNA (mtDNA)-targeted therapies. Exosomes, which are nanoscale, naturally occurring extracellular vesicles (EVs), have been employed for biotechnology applications in oligonucleotide delivery in recent years. We discovered that exosomes from fetal bovine serum (FBS) can be used as a simple and biologically compatible delivery agent of 2'-OMe RNA antisense oligonucleotides to cellular mitochondria, leading to target protein knockdown. While most RNA interference and antisense mechanisms occur in the cytoplasm or nucleus, the need for mitochondrial targeting has become increasingly apparent. Mitochondrial disease describes a variety of currently incurable syndromes that especially affect organs requiring significant energy including the muscles, heart, and brain. Many of these syndromes result from mutations in mtDNA, which codes for the 13 proteins of the oxidative phosphorylation system and are thus often implicated in inherited metabolic disorders.
2025-03-21 | Chromogen-based double immunohistochemical detection of mitochondrial respiratory chain deficiencies in human brain tissue.
Studies of the mitochondrial respiratory chain (MRC) have given important insights into the pathology of mitochondrial and neurodegenerative disorders. Immunohistochemical methods for staining MRC complexes are particularly valuable for assessing quantitative changes in situ, especially in complex tissues with cellular heterogeneity, such as the brain. However, traditional approaches have notable limitations. Chromogen-based staining, while preserving tissue morphology, has been restricted to a single antigen per section, preventing co-assessment of MRC complexes and mitochondrial mass on the same section. Immunofluorescence, which allows multiplex staining of multiple targets, partially addresses this limitation but compromises tissue morphology and can be highly variable in postmortem brain samples. To address these challenges, we have established a dual-antigen, chromogen-based immunohistochemical method that allows simultaneous assessment of each MRC complex and the mitochondrial marker voltage-dependent anion channel 1 (VDAC1) on the same section. As proof of concept, we apply this method on brain tissue from patients with neurological disease caused by mutations in the mitochondrial DNA polymerase gamma (POLG). Our findings demonstrate that this approach is both reliable and robust. Moreover, this method enables more precise identification of MRC deficiencies in neurons and significantly reduces the amount of tissue required for analysis, a critical advantage when working with scarce human brain samples.
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Drug Discovery Landscape
5 orphan drug designations for Mitochondrial disease.
5 orphan drug designations for Mitochondrial disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Methyl 4-{[2-(acetamino)ethyl]sulfanyl}-4-oxobutanoate | small molecules | FDA | Pharming Technologies BV | |
zagociguat | small molecules | FDA | Tisento Therapeutics, Inc. | |
vatiquinone | small molecules | FDA | PTC Therapeutics, Inc. | |
uridine triacetate | small molecules | FDA | Pharma Cinq, LLC | |
2',3',5'-tri-o-acetyluridine | small molecules | FDA | Repligen Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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