RARE DISEASE
MELAS
MELAS
MELAS
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Drug discovery
8
drugs
With orphan designations
Overview
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes) is a maternally inherited mitochondrial disorder characterized by progressive encephalomyopathy, stroke-like episodes (e.g., hemiparesis, cortical blindness), lactic acidosis, and multiorgan involvement. It arises from mitochondrial DNA mutations, most commonly MT-TL1 (80% of cases). Diagnosis relies on clinical features, neuroimaging showing non-vascular infarcts, elevated lactate, and genetic testing. Management is supportive, focusing on symptom control and preventing metabolic crises [1][5][7].
Burden
Progressive neurologic decline, with 40–90% developing dementia and 71–96% epilepsy [2][5].
Median survival ~17 years post-symptom onset; mortality linked to stroke-like events or multisystem failure [7][12].
High healthcare utilization due to recurrent hospitalizations and lifelong multidisciplinary care needs [5][12].
Therapies
Acute care: IV L-arginine for stroke-like episodes; seizure management avoiding valproate [3][7].
Chronic management: Coenzyme Q10, antioxidants, and cochlear implants for hearing loss [7][12].
Multidisciplinary support: Diabetes management, cardiac surveillance, and neurologic rehabilitation [3][7].
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare transplant-related disorders
Research Papers
521 drug discovery papers about MELAS, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
521 drug discovery papers about MELAS, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
A 67-year-old male with Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS) who developed life-threatening Stevens-Johnson Syndrome (SJS) more than one month after initiating lamotrigine (LTG) for epilepsy management. Despite prompt LTG discontinuation and aggressive immunomodulatory therapy, the patient succumbed to severe infection and multiple organ failure. LTG-induced SJS is associated with multiple risk factors. The immune-activating microenvironment resulting from mitochondrial dysfunction may potentiate the risk of LTG-induced SJS. Lamotrigine should be used cautiously for epilepsy in high-risk patients, particularly those with mitochondrial encephalomyopathy (ME), and comprehensive evaluation is required to minimize severe hypersensitivity reactions.
2026-07-28 | L-citrulline treatment of nitric oxide deficiency in MELAS a phase I dose-finding and safety study.
There is evidence that nitric oxide deficiency occurs in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and may result in impaired blood perfusion in small blood vessels, contributing to stroke-like episodes (SLEs). The primary aim of this phase one study was to estimate the maximum tolerated dose (MTD) of L-citrulline in adults with MELAS. The primary safety outcome was the occurrence of a dose limiting toxicity (DLT) in the first eight weeks after treatment initiation. Secondary outcomes included changes in cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and plasma citrulline, arginine, and ornithine levels from baseline to end of treatment (week four). Plasma guanidino compounds were assessed from baseline to week one for potential arginine toxicity and plasma lactate and alanine from baseline to end of treatment as pharmacodynamic biomarkers. Ten consecutive patients were screened, enrolled and assigned to the following doses: 10 g (n = 1), 20 g (n = 1), 30 g (n = 2), and 40 g (n = 6). There were no DLTs observed with any of the doses. However, analysis of plasma guanidino compounds demonstrated analyte outliers (Z-scores >2) with higher doses of L-citrulline (30 and 40 g). CBF increased from baseline in seven study participants, six of whom were on the highest dose. The highest CBF increase was observed in the occipital region. With the highest dose of L-citrulline, substantial increases in plasma arginine and citrulline were observed at week four when compared to baseline. While no DLTs were observed, the increase of guanidino compounds with 30 g and 40 g of L-citrulline needs to be further interrogated with serial measurements in a future study to ensure safety of these doses and determine whether the increase is sustained long term. A randomized placebo-controlled trial will be required to evaluate the efficacy of L-citrulline in individuals with MELAS.
gene therapies
2026-08-01 | From mitochondria to arrhythmia: Rare phenotype of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes presenting with long QT type 3 pattern
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare, mitochondrial-inherited, multisystem disorder often presenting early in life with unexplained headaches, seizures, myopathy, neurologic deficits, early onset diabetes, and profound lactic acidosis1. The diverse clinical manifestations of mitochondrial disease reflect the role of mitochondria in cellular energy production and their ubiquitous presence throughout the body.
2026-07-16 | MELAS syndrome: a case report
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in mitochondrial genes characterized by metabolic stroke, seizures, cognitive decline, lactic acidosis, ragged-red fibers, headache, vomiting and in 80% of cases it occurs due to the mtDNA variant m.3243A>G. Here, we present case history of a 17-year-old boy who was diagnosed with MELAS syndrome, whose brain magnetic resonance spectroscopy showed decreased N-acetylaspartate and choline peak and markedly increased lipid and lactate peak. Genetic study revealed positive mutation variant in subunit-5 of the respiratory chain (MT-ND5) which is reported in MELAS. BIRDEM Med J 2026; 16(2): 100-103
2026-07-02 | Analysis of acute stroke-like lesions in MELAS: Distribution, potential boundaries and spreading pattern.
Imaging during acute episodes of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) primarily shows reversible cortical edema. However, the mechanisms underlying such cortical lesions in MELAS remain unclear. Analyzing MRI findings of MELAS could provide clues to these mechanisms. We reviewed the medical records and imaging data of MELAS patients treated at Peking University First Hospital from 2013 to 2024. 61 MRI scans from 55 patients were included in this study. The spatial distribution of SLLs was analyzed based on high-resolution cortical segmentation. Next, we established a non-negative independent component analysis (nnICA) model to separate independent SLL components. Then we assessed correlation of synaptic density and lesion load using Spearman's rho test. Finally, a simple diffusion model was used to fit the spreading behavior of SLLs. The cortical probability map shows a peak involvement frequency of 0.46 observed in the left temporo-occipital lobe. Distribution of SLLs showed no bias between left and right hemisphere. Then we identified 8 independent cortical components of SLLs. The Probability Map showed a positive correlation with synaptic density map (Spearman's rho = 0.32, p < 0.001). Additionally, the Directed-Effect Coefficient exhibited a good proportional relationship with the Dilation Coefficient (y = 0.50x+0.00, r = 0.76). Analysis of structural MRI data suggests that MELAS SLLs exhibit a pattern of free spreading within regions and restricted spreading between regions on the cortex. The identified components indicate the presence of potential boundaries. We also showed that lesion spreading was often hindered in areas with sparse synaptic density.
2026-06-18 | Diagnostic and therapeutic considerations in m.3243A>G-associated chronic intestinal pseudo-obstruction.
We read with interest the article by Zhang et al. about an 18-year-old female carrier of the m.3243A>G variant in the MT-TL1 gene. Clinically, the mutation manifested as MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and chronic intestinal pseudo-obstruction (CIPO). Despite surgical (colostomy) and conservative measures (enemas, prokinetics, jejunal nutrition, mitochondrial therapy), the CIPO worsened, and the patient ultimately died of multiple organ failure. The study is promising, but some points require discussion.
2026-05-18 | Cerebral vasodilation and lesion patterns in stroke-like episodes of MELAS: a quantitative angiographic investigation.
The pathophysiology of stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome remains incompletely understood, despite the syndrome's distinctive clinical and radiological characteristics. This study aimed to gain insight into the underlying mechanisms of stroke-like episodes by analyzing vascular and perfusion changes during acute stroke-like episodes. We conducted a retrospective observational study of genetically confirmed MELAS patients who experienced stroke-like episodes between January 2010 and December 2023. All patients underwent magnetic resonance imaging (MRI) and angiography during the acute phase. Vessel diameters were quantitatively measured at predefined anatomical locations on both the affected and contralateral sides, and were compared using the Wilcoxon signed-rank test. Follow-up imaging was reviewed when available to assess the reversibility of vascular changes. Among the 17 patients, 15 (88.2%) exhibited lesions characterized by cortical cytotoxic edema and subcortical vasogenic edema. Angiographic analysis revealed significant vasodilation of major vessels in 10 patients (58.8%), primarily affecting the middle cerebral artery (MCA) on the symptomatic side. Hyperperfusion was observed in all patients who underwent perfusion-weighted MRI, which spatially corresponded to stroke-like lesions. Quantitative analysis indicated a significant difference in vessel diameter between the affected [1.92 (interquartile range, 1.76-2.42)] and unaffected sides [1.84 (interquartile range, 1.74-2.22), Z=-2.250, P=0.024]. Follow-up angiography was conducted for three patients, all of whom demonstrated complete resolution of vasodilation. Our findings of cortical cytotoxic edema, subcortical vasogenic edema, and reversible major vessel vasodilation during stroke-like episodes contribute to the pathophysiological understanding of MELAS based on mitochondrial energy failure.
proteins
2026-04-19 | Glucagon-Like Peptide-1 Receptor Agonists in the Management of Mitochondrial Diabetes in an Adolescent: A Case Report.
Mitochondrial diabetes is rare and typically treated with dietary intervention and oral hypoglycaemic agents. Most require insulin. Novel treatments are available but are not well characterised. A 16-year-old adolescent girl with a genetically confirmed diagnosis of MELAS due to an m.3243A>G variant presented with clinical and biochemical features of diabetes. She was successfully transitioned from subcutaneous insulin therapy to weekly GLP-1RA monotherapy shortly after diagnosis of diabetes. Treatment with 0.25 mg semaglutide SC weekly led to a reduction in HbA1c from 13.7% (126 mmol/mol) to 5.6% (38 mmol/mol) over a 7-month period. Insulin was completely ceased within 5 days of starting semaglutide. CGM data from a 11 months follow-up period are presented, which demonstrate CGM data meeting glycaemic targets. Low-dose semaglutide 0.25 mg sc weekly was efficacious and well tolerated without lactic acidosis. Use of GLP-1RA could be considered a novel and effective treatment in the pharmacological management of paediatric mitochondrial diabetes.
2026-01-28 | Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides.
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator at an 8-bp DNA element. This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJk). Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJk and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJk interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.
2025-11-03 | Abstract 4370064: Cardioembolic Stroke in MELAS Treated with Thrombolysis
Background: MELAS is a rare mitochondrial disorder characterized by multisystem involvement, including stroke-like episodes, seizures, and cardiomyopathy. Cardiac involvement in MELAS may include left ventricular dysfunction, arrhythmias, and structural abnormalities, yet the occurrence of cardioembolic stroke as a direct consequence of these manifestations is exceedingly rare. To date, no literature has clearly described this association. Case Presentation: A male in his twenties with known MELAS syndrome, epilepsy, and heart failure with reduced ejection fraction (EF 25%) presented with acute right hemiparesis and aphasia. Investigations: CT angiography and CT perfusion revealed reduced opacification in the left MCA bifurcation and a left M2 thrombus (Figure 1A). The contrast echocardiogram showed a normal-sized left ventricle with severely reduced ejection fraction (25%, down from 30% six months prior), diffuse hypokinesis, grade III diastolic dysfunction, and a left ventricular thrombus, with no patent foramen ovale. Treatment: Given the high suspicion for cardioembolic stroke, the patient received intravenous tenecteplase within the 3-hour window. Mechanical thrombectomy was planned but aborted due to spontaneous recanalization. Post-thrombolytic angiography confirmed reperfusion of the left MCA with residual distal M3 thrombus (Figure 1B).MRI confirmed infarcts in the left MCA distribution and right precentral gyrus, with no evidence of hemorrhagic transformation. Anticoagulation was initiated for secondary prevention. Statins were withheld due to concerns about mitochondrial toxicity. Follow-up: On a 3-month follow-up, the patient remained neurologically stable and continued oral anticoagulation without recurrent events. Discussion: The clinical scenario posed a diagnostic challenge—stroke-like episodes in MELAS are metabolic and typically non-territorial. However, an LV thrombus, territorial infarction, and perfusion mismatch pointed to an ischemic etiology. Timely thrombolysis led to significant neurological recovery. This case highlights the importance of distinguishing cardioembolic stroke from mitochondrial stroke-like events, especially in patients with known cardiac involvement. Conclusion: In MELAS patients with cardiac dysfunction, cardioembolic stroke must be considered when clinical and imaging findings suggest a vascular event. Early recognition and intervention, including thrombolysis, can lead to favorable outcomes.
2025-08-12 | Peptide-mimetics derived from leucyl-tRNA synthetase are potential agents for the therapy of mt-tRNA related diseases.
Mitochondrial diseases caused by point mutations in mitochondrial tRNA (mt-tRNA) genes, including MELAS and MERRF syndromes, represent a significant unmet clinical need, due to the lack of effective treatments. We previously identified peptide molecules derived from human leucyl-tRNA synthetase, whose features make them attractive leads for the development of therapeutic agents against mt-tRNA point mutations-related diseases. Indeed, we demonstrated that, upon exogenous administration, these peptides penetrate human cell and mitochondrial membranes; stabilize mitochondrial tRNA structures; and rescue severe mitochondrial defects in cells bearing the point mutations m.3243A>G and m.8344A>G, responsible for MELAS and MERRF syndromes, respectively. To progress towards therapeutic applications, in this work we designed three peptide-mimetic derivatives (PMTs). These are composed entirely of D-amino acids and potentially endowed with enhanced stability in human plasma and resistance to enzymatic degradation. We show that, like the parent peptide, the PMTs have mitochondrial localization and improve cell viability and oxygen consumption in human cybrid cell lines bearing the aforementioned point mutations. Additionally, as anticipated, the PMTs had significantly higher plasma stability than the parent peptide. The most promising PMT was radiolabelled with Cu-64 and used in in vivo biodistribution and tolerability studies. Importantly, i. v. administered PMT reached all body districts, including heart, muscle and even brain, thus revealing an intrinsic ability to cross the blood-brain barrier. Finally, PMT was safe in adult wild-type mice at dosages up to 10 mg/kg. These findings represent a significant step towards the implementation of therapeutic strategies for mttRNA-related mitochondrial diseases.
2023-12-18 | Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology.
Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA structure would also stabilize its pathogenic variants is unknown. Here we show that the N 1 -methylation of guanosine at position 9 (m 1 G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m 1 G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that the N 1 -methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
cell therapies
2026-07-28 | Long-term donor and graft safety despite subclinical mitochondrial abnormalities: mechanistic insights from a 22-year follow-up of a carrier-to-MELAS kidney transplant
Ideally, deceased donor kidney transplantation is preferred for patients with mitochondrial nephropathy caused by the m.3243 A > G mutation to avoid genetic risks. However, in regions where deceased donation is limited and living donation predominates, such as Japan, family members are often the only available donors. The safety of using maternal relatives, who are obligate carriers of the mutation, remains highly controversial due to the risk of unmasking renal failure in both the donor and the allograft. We report a 22-year follow-up of an inadvertent living kidney transplant from a 55-year-old mother to her 26-year-old daughter. The recipient presented with MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) and end-stage kidney disease due to focal segmental glomerulosclerosis (FSGS), with the m.3243 A > G mutation confirmed prior to transplantation. Conversely, the donor mother was phenotypically normal regarding renal function without diabetes, and conventional genetic testing at the time failed to detect the mutation. Consequently, the recipient’s mutation was presumed to be de novo, allowing the donation to proceed. Notably, the donor’s zero-hour allograft biopsy revealed ultrastructural mitochondrial abnormalities but no overt light microscopic damage (i.e., no FSGS). At 22 years post-transplant, both the recipient’s graft function (serum creatinine 1.16 mg/dL, albuminuria 5.0 mg/gCr) and the donor’s remaining kidney function (serum creatinine 0.98 mg/dL, albuminuria 10.4 mg/gCr) remain excellent. Current highly sensitive genetic analysis revealed an extremely low blood heteroplasmy in the donor (0.1%) compared to 20% in the recipient, demonstrating a severe “genetic bottleneck” effect. Furthermore, the recipient’s older sister was found to have a 4% mutational load, definitively confirming maternal inheritance rather than a de novo mutation. This case represents the longest reported follow-up of a living kidney transplant from an m.3243 A > G carrier. It demonstrates that maternal carriers with extremely low heteroplasmy and no light microscopic evidence of overt renal damage on biopsy can be safe donors and provide excellent long-term graft outcomes. Precise risk stratification based on genotype and biopsy findings, rather than uniform exclusion, may expand transplant options.
2026-06-20 | Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) represents a multisystemic mitochondrial disease mainly triggered by heteroplasmic m.3243A > G mutation in mtDNA MT-TL1, the gene for tRNA^Leu(UUR). Here we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a female MELAS patient into induced pluripotent stem cells (iPSCs). This patient-specific iPSC line provides a valuable platform to investigate MELAS pathophysiology and screen therapeutic interventions targeting mitochondrial dysfunction in a genetically relevant context.
2026-06-10 | Cochlear implantation in MELAS syndrome: a systematic review of audiological outcomes, surgical considerations, and clinical implications
Abstract Purpose Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder frequently associated with sensorineural hearing loss (SNHL). Due to mitochondrial dysfunction, cochlear structures, especially the stria vascularis and outer hair cells, are susceptible to damage, causing progressive hearing impairment. Cochlear implantation (CI) offers rehabilitative potential, yet unique perioperative challenges related to anesthetic sensitivity and metabolic instability require tailored management strategies. Limited evidence exists regarding CI outcomes specifically in MELAS patients. This systematic review critically evaluates existing literature on CI efficacy, audiological outcomes, and perioperative considerations in MELAS. Methods A comprehensive systematic review following PRISMA guidelines was conducted. Databases including PubMed, Embase, Web of Science, and Scopus were searched for relevant studies reporting outcomes of CI in MELAS patients. Two independent reviewers performed article screening, data extraction, and risk-of-bias assessment. Results From 292 retrieved studies, 8 studies ( n = 10 patients) were included. Audiological outcomes consistently showed substantial improvement in speech perception tests post-CI. Standardized assessments demonstrated enhanced sentence and word recognition, alongside improved auditory-evoked potentials (ABR, MLR). Patients reported improvement in social engagement and communication. Surgical interventions were successful despite unique perioperative challenges related to MELAS pathology, including anesthesia complications and metabolic crises. However, existing studies primarily consisted of individual case reports, limiting generalizability. Conclusion Cochlear implantation is an effective rehabilitative option for patients with MELAS syndrome and severe-to-profound sensorineural hearing loss, improving speech perception and communication. Audiological outcomes and electrophysiological measures support its role in restoring auditory function in this unique population. However, given the risks of metabolic decompensation, anesthetic sensitivity, and perioperative electrolyte disturbances in MELAS, careful planning of anesthesia and surgical protocols is critical to patient safety.
2026-04-24 | iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder primarily caused by a heteroplasmic point mutation at mitochondrial DNA (mtDNA) position 3243 (m.3243A > G) in the MT-TL1 gene, which encodes mitochondrial tRNA^Leu(UUR). In this study, we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a male patient diagnosed with MELAS into induced pluripotent stem cells (iPSCs). This patient-specific iPSC platform enables investigation into the relationship between heteroplasmy levels and disease manifestation and provides a valuable tool for screening potential therapeutic strategies aimed at mitigating mitochondrial dysfunction in MELAS.
2026-02-09 | Case Report: Simultaneous pancreas-kidney transplantation in MELAS: first reported case with 5-year follow-up.
Mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial DNA disorder that, in severe cases, can result in insulin-dependent diabetes and end-stage renal disease (ESRD). While organ transplantation is a potential treatment, documented cases remain scarce. A 40-year-old patient with dialysis-dependent ESRD and diabetes secondary to MELAS underwent simultaneous pancreas-kidney transplantation. The perioperative and postoperative periods were uncomplicated with only targeted MELAS-specific adaptations to standard protocols. During the 5-year follow-up, the patient maintained excellent kidney allograft function and sustained insulin independence, with no need for dialysis or exogenous insulin therapy. At 5 years, creatinine was 77 µmol/L with an estimated GFR above 90 mL/min/1.73 m2, and glycated hemoglobin was 40 mmol/mol. SPK transplantation may be feasible in carefully selected patients with MELAS, ESRD, and diabetes, providing durable renal and metabolic graft function at 5 years. To our knowledge, this is the first reported SPK case in MELAS, with extended follow-up.
other
2025-05-09 | Genetic migraine disorders and the response to calcitonin gene-related peptide antagonist treatment.
Calcitonin gene-related peptide (CGRP) is a potent cerebral vasodilator and part of the trigeminal migraine cascade. Newer migraine therapies target CGRP signaling for both acute and preventative management of headache. In this series, we present two cases of genetic conditions, of which migraine is a key feature, responsive to CGRP antagonist therapy. A 31-year-old female with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and a phenotype of chronic migraine with visual aura, and a 62-year-old female with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with a phenotype of chronic migraine and side-locked headache with cranial autonomic symptoms. Each experienced a significant reduction in the frequency of their migraine attacks with monoclonal antibody treatment against CGRP. In this case series, we add to the growing body of evidence that CGRP-blocking medications are safe and effective in some heritable neurological disorders in which vasomodulation is a common underlying pathology. To our knowledge, we present the first cases of galcanezumab use in an individual with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and eptinezumab in an individual with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
2024-02-22 | Collision-Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial Transfer Ribonucleic Acids.
Ribonucleic acids (RNAs) remain challenging targets for structural biology, creating barriers to understanding their vast functions in cellular biology and fully realizing their applications in biotechnology. The inherent dynamism of RNAs creates numerous obstacles in capturing their biologically relevant higher-order structures (HOSs), and as a result, many RNA functions remain unknown. In this study, we describe the development of native ion mobility-mass spectrometry and collision-induced unfolding (CIU) for the structural characterization of a variety of RNAs. We evaluate the ability of these techniques to preserve native structural features in the gas phase across a wide range of functional RNAs. Finally, we apply these tools to study the elusive mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes-associated A3243G mutation. Our data demonstrate that our experimentally determined conditions preserve some solution-state memory of RNAs via the correlated complexity of CIU fingerprints and RNA HOS, the observation of predicted stability shifts in the control RNA samples, and the retention of predicted magnesium binding events in gas-phase RNA ions. Significant differences in collision cross section and stability are observed as a function of the A3243G mutation across a subset of the mitochondrial tRNA maturation pathway. We conclude by discussing the potential application of CIU for the development of RNA-based biotherapeutics and, more broadly, transcriptomic characterization.
2023-09-08 | Collision Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial tRNAs
Ribonucleic acids (RNAs) remain challenging targets for structural biology, creating barriers to understanding their vast functions in cellular biology and fully realizing their applications in biotechnology. The inherent dynamism of RNAs creates numerous obstacles in capturing their biologically relevant higher-order structures (HOSs), and as a result, many RNA functions remain unknown. In this report, we describe the development of native ion mobility-mass spectrometry (IM-MS) and collision induced unfolding (CIU) for the structural characterization of a variety of RNAs. We evaluate the ability of these techniques to preserve native structural features into the gas-phase across a wide range of functional RNAs. Finally, we apply these tools to study the elusive mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)-associated A3243G mutation. Our data demonstrate that our experimentally determined conditions preserve some solution-state memory of RNA via the increasing complexity of CIU fingerprints by RNA HOS and the retention of predicted magnesium binding events. Relating to the role of MELAS-inducing mutations in mitochondrial trans-fer RNA (mt-tRNAs), significant differences in collision cross-section (CCS) and stability are observed as a function of the A3243G mutation across a subset of the mitochondrial transfer RNA (tRNA) maturation pathway. We conclude by discussing the potential application of CIU for the development of RNA-based biotherapeutics and, more broadly, transcriptomic characterization.
2023-09-03 | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease
In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeuUUR and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development.
2019-11-13 | Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation
Translation fidelity is crucial for prokaryotes and eukaryotic nuclear-encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error-prone and hyper-accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian-specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.
small molecules
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.
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
A 67-year-old male with Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS) who developed life-threatening Stevens-Johnson Syndrome (SJS) more than one month after initiating lamotrigine (LTG) for epilepsy management. Despite prompt LTG discontinuation and aggressive immunomodulatory therapy, the patient succumbed to severe infection and multiple organ failure. LTG-induced SJS is associated with multiple risk factors. The immune-activating microenvironment resulting from mitochondrial dysfunction may potentiate the risk of LTG-induced SJS. Lamotrigine should be used cautiously for epilepsy in high-risk patients, particularly those with mitochondrial encephalomyopathy (ME), and comprehensive evaluation is required to minimize severe hypersensitivity reactions.
2026-07-28 | L-citrulline treatment of nitric oxide deficiency in MELAS a phase I dose-finding and safety study.
There is evidence that nitric oxide deficiency occurs in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and may result in impaired blood perfusion in small blood vessels, contributing to stroke-like episodes (SLEs). The primary aim of this phase one study was to estimate the maximum tolerated dose (MTD) of L-citrulline in adults with MELAS. The primary safety outcome was the occurrence of a dose limiting toxicity (DLT) in the first eight weeks after treatment initiation. Secondary outcomes included changes in cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and plasma citrulline, arginine, and ornithine levels from baseline to end of treatment (week four). Plasma guanidino compounds were assessed from baseline to week one for potential arginine toxicity and plasma lactate and alanine from baseline to end of treatment as pharmacodynamic biomarkers. Ten consecutive patients were screened, enrolled and assigned to the following doses: 10 g (n = 1), 20 g (n = 1), 30 g (n = 2), and 40 g (n = 6). There were no DLTs observed with any of the doses. However, analysis of plasma guanidino compounds demonstrated analyte outliers (Z-scores >2) with higher doses of L-citrulline (30 and 40 g). CBF increased from baseline in seven study participants, six of whom were on the highest dose. The highest CBF increase was observed in the occipital region. With the highest dose of L-citrulline, substantial increases in plasma arginine and citrulline were observed at week four when compared to baseline. While no DLTs were observed, the increase of guanidino compounds with 30 g and 40 g of L-citrulline needs to be further interrogated with serial measurements in a future study to ensure safety of these doses and determine whether the increase is sustained long term. A randomized placebo-controlled trial will be required to evaluate the efficacy of L-citrulline in individuals with MELAS.
gene therapies
2026-08-01 | From mitochondria to arrhythmia: Rare phenotype of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes presenting with long QT type 3 pattern
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare, mitochondrial-inherited, multisystem disorder often presenting early in life with unexplained headaches, seizures, myopathy, neurologic deficits, early onset diabetes, and profound lactic acidosis1. The diverse clinical manifestations of mitochondrial disease reflect the role of mitochondria in cellular energy production and their ubiquitous presence throughout the body.
2026-07-16 | MELAS syndrome: a case report
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in mitochondrial genes characterized by metabolic stroke, seizures, cognitive decline, lactic acidosis, ragged-red fibers, headache, vomiting and in 80% of cases it occurs due to the mtDNA variant m.3243A>G. Here, we present case history of a 17-year-old boy who was diagnosed with MELAS syndrome, whose brain magnetic resonance spectroscopy showed decreased N-acetylaspartate and choline peak and markedly increased lipid and lactate peak. Genetic study revealed positive mutation variant in subunit-5 of the respiratory chain (MT-ND5) which is reported in MELAS. BIRDEM Med J 2026; 16(2): 100-103
2026-07-02 | Analysis of acute stroke-like lesions in MELAS: Distribution, potential boundaries and spreading pattern.
Imaging during acute episodes of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) primarily shows reversible cortical edema. However, the mechanisms underlying such cortical lesions in MELAS remain unclear. Analyzing MRI findings of MELAS could provide clues to these mechanisms. We reviewed the medical records and imaging data of MELAS patients treated at Peking University First Hospital from 2013 to 2024. 61 MRI scans from 55 patients were included in this study. The spatial distribution of SLLs was analyzed based on high-resolution cortical segmentation. Next, we established a non-negative independent component analysis (nnICA) model to separate independent SLL components. Then we assessed correlation of synaptic density and lesion load using Spearman's rho test. Finally, a simple diffusion model was used to fit the spreading behavior of SLLs. The cortical probability map shows a peak involvement frequency of 0.46 observed in the left temporo-occipital lobe. Distribution of SLLs showed no bias between left and right hemisphere. Then we identified 8 independent cortical components of SLLs. The Probability Map showed a positive correlation with synaptic density map (Spearman's rho = 0.32, p < 0.001). Additionally, the Directed-Effect Coefficient exhibited a good proportional relationship with the Dilation Coefficient (y = 0.50x+0.00, r = 0.76). Analysis of structural MRI data suggests that MELAS SLLs exhibit a pattern of free spreading within regions and restricted spreading between regions on the cortex. The identified components indicate the presence of potential boundaries. We also showed that lesion spreading was often hindered in areas with sparse synaptic density.
2026-06-18 | Diagnostic and therapeutic considerations in m.3243A>G-associated chronic intestinal pseudo-obstruction.
We read with interest the article by Zhang et al. about an 18-year-old female carrier of the m.3243A>G variant in the MT-TL1 gene. Clinically, the mutation manifested as MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and chronic intestinal pseudo-obstruction (CIPO). Despite surgical (colostomy) and conservative measures (enemas, prokinetics, jejunal nutrition, mitochondrial therapy), the CIPO worsened, and the patient ultimately died of multiple organ failure. The study is promising, but some points require discussion.
2026-05-18 | Cerebral vasodilation and lesion patterns in stroke-like episodes of MELAS: a quantitative angiographic investigation.
The pathophysiology of stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome remains incompletely understood, despite the syndrome's distinctive clinical and radiological characteristics. This study aimed to gain insight into the underlying mechanisms of stroke-like episodes by analyzing vascular and perfusion changes during acute stroke-like episodes. We conducted a retrospective observational study of genetically confirmed MELAS patients who experienced stroke-like episodes between January 2010 and December 2023. All patients underwent magnetic resonance imaging (MRI) and angiography during the acute phase. Vessel diameters were quantitatively measured at predefined anatomical locations on both the affected and contralateral sides, and were compared using the Wilcoxon signed-rank test. Follow-up imaging was reviewed when available to assess the reversibility of vascular changes. Among the 17 patients, 15 (88.2%) exhibited lesions characterized by cortical cytotoxic edema and subcortical vasogenic edema. Angiographic analysis revealed significant vasodilation of major vessels in 10 patients (58.8%), primarily affecting the middle cerebral artery (MCA) on the symptomatic side. Hyperperfusion was observed in all patients who underwent perfusion-weighted MRI, which spatially corresponded to stroke-like lesions. Quantitative analysis indicated a significant difference in vessel diameter between the affected [1.92 (interquartile range, 1.76-2.42)] and unaffected sides [1.84 (interquartile range, 1.74-2.22), Z=-2.250, P=0.024]. Follow-up angiography was conducted for three patients, all of whom demonstrated complete resolution of vasodilation. Our findings of cortical cytotoxic edema, subcortical vasogenic edema, and reversible major vessel vasodilation during stroke-like episodes contribute to the pathophysiological understanding of MELAS based on mitochondrial energy failure.
proteins
2026-04-19 | Glucagon-Like Peptide-1 Receptor Agonists in the Management of Mitochondrial Diabetes in an Adolescent: A Case Report.
Mitochondrial diabetes is rare and typically treated with dietary intervention and oral hypoglycaemic agents. Most require insulin. Novel treatments are available but are not well characterised. A 16-year-old adolescent girl with a genetically confirmed diagnosis of MELAS due to an m.3243A>G variant presented with clinical and biochemical features of diabetes. She was successfully transitioned from subcutaneous insulin therapy to weekly GLP-1RA monotherapy shortly after diagnosis of diabetes. Treatment with 0.25 mg semaglutide SC weekly led to a reduction in HbA1c from 13.7% (126 mmol/mol) to 5.6% (38 mmol/mol) over a 7-month period. Insulin was completely ceased within 5 days of starting semaglutide. CGM data from a 11 months follow-up period are presented, which demonstrate CGM data meeting glycaemic targets. Low-dose semaglutide 0.25 mg sc weekly was efficacious and well tolerated without lactic acidosis. Use of GLP-1RA could be considered a novel and effective treatment in the pharmacological management of paediatric mitochondrial diabetes.
2026-01-28 | Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides.
Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator at an 8-bp DNA element. This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJk). Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJk and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJk interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.
2025-11-03 | Abstract 4370064: Cardioembolic Stroke in MELAS Treated with Thrombolysis
Background: MELAS is a rare mitochondrial disorder characterized by multisystem involvement, including stroke-like episodes, seizures, and cardiomyopathy. Cardiac involvement in MELAS may include left ventricular dysfunction, arrhythmias, and structural abnormalities, yet the occurrence of cardioembolic stroke as a direct consequence of these manifestations is exceedingly rare. To date, no literature has clearly described this association. Case Presentation: A male in his twenties with known MELAS syndrome, epilepsy, and heart failure with reduced ejection fraction (EF 25%) presented with acute right hemiparesis and aphasia. Investigations: CT angiography and CT perfusion revealed reduced opacification in the left MCA bifurcation and a left M2 thrombus (Figure 1A). The contrast echocardiogram showed a normal-sized left ventricle with severely reduced ejection fraction (25%, down from 30% six months prior), diffuse hypokinesis, grade III diastolic dysfunction, and a left ventricular thrombus, with no patent foramen ovale. Treatment: Given the high suspicion for cardioembolic stroke, the patient received intravenous tenecteplase within the 3-hour window. Mechanical thrombectomy was planned but aborted due to spontaneous recanalization. Post-thrombolytic angiography confirmed reperfusion of the left MCA with residual distal M3 thrombus (Figure 1B).MRI confirmed infarcts in the left MCA distribution and right precentral gyrus, with no evidence of hemorrhagic transformation. Anticoagulation was initiated for secondary prevention. Statins were withheld due to concerns about mitochondrial toxicity. Follow-up: On a 3-month follow-up, the patient remained neurologically stable and continued oral anticoagulation without recurrent events. Discussion: The clinical scenario posed a diagnostic challenge—stroke-like episodes in MELAS are metabolic and typically non-territorial. However, an LV thrombus, territorial infarction, and perfusion mismatch pointed to an ischemic etiology. Timely thrombolysis led to significant neurological recovery. This case highlights the importance of distinguishing cardioembolic stroke from mitochondrial stroke-like events, especially in patients with known cardiac involvement. Conclusion: In MELAS patients with cardiac dysfunction, cardioembolic stroke must be considered when clinical and imaging findings suggest a vascular event. Early recognition and intervention, including thrombolysis, can lead to favorable outcomes.
2025-08-12 | Peptide-mimetics derived from leucyl-tRNA synthetase are potential agents for the therapy of mt-tRNA related diseases.
Mitochondrial diseases caused by point mutations in mitochondrial tRNA (mt-tRNA) genes, including MELAS and MERRF syndromes, represent a significant unmet clinical need, due to the lack of effective treatments. We previously identified peptide molecules derived from human leucyl-tRNA synthetase, whose features make them attractive leads for the development of therapeutic agents against mt-tRNA point mutations-related diseases. Indeed, we demonstrated that, upon exogenous administration, these peptides penetrate human cell and mitochondrial membranes; stabilize mitochondrial tRNA structures; and rescue severe mitochondrial defects in cells bearing the point mutations m.3243A>G and m.8344A>G, responsible for MELAS and MERRF syndromes, respectively. To progress towards therapeutic applications, in this work we designed three peptide-mimetic derivatives (PMTs). These are composed entirely of D-amino acids and potentially endowed with enhanced stability in human plasma and resistance to enzymatic degradation. We show that, like the parent peptide, the PMTs have mitochondrial localization and improve cell viability and oxygen consumption in human cybrid cell lines bearing the aforementioned point mutations. Additionally, as anticipated, the PMTs had significantly higher plasma stability than the parent peptide. The most promising PMT was radiolabelled with Cu-64 and used in in vivo biodistribution and tolerability studies. Importantly, i. v. administered PMT reached all body districts, including heart, muscle and even brain, thus revealing an intrinsic ability to cross the blood-brain barrier. Finally, PMT was safe in adult wild-type mice at dosages up to 10 mg/kg. These findings represent a significant step towards the implementation of therapeutic strategies for mttRNA-related mitochondrial diseases.
2023-12-18 | Post-Transcriptional Methylation of Mitochondrial-tRNA Differentially Contributes to Mitochondrial Pathology.
Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA structure would also stabilize its pathogenic variants is unknown. Here we show that the N 1 -methylation of guanosine at position 9 (m 1 G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has an opposite and destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated by the observation that demethylation of m 1 G9, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving its structure and activity. These results have new therapeutic implications, suggesting that the N 1 -methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
cell therapies
2026-07-28 | Long-term donor and graft safety despite subclinical mitochondrial abnormalities: mechanistic insights from a 22-year follow-up of a carrier-to-MELAS kidney transplant
Ideally, deceased donor kidney transplantation is preferred for patients with mitochondrial nephropathy caused by the m.3243 A > G mutation to avoid genetic risks. However, in regions where deceased donation is limited and living donation predominates, such as Japan, family members are often the only available donors. The safety of using maternal relatives, who are obligate carriers of the mutation, remains highly controversial due to the risk of unmasking renal failure in both the donor and the allograft. We report a 22-year follow-up of an inadvertent living kidney transplant from a 55-year-old mother to her 26-year-old daughter. The recipient presented with MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) and end-stage kidney disease due to focal segmental glomerulosclerosis (FSGS), with the m.3243 A > G mutation confirmed prior to transplantation. Conversely, the donor mother was phenotypically normal regarding renal function without diabetes, and conventional genetic testing at the time failed to detect the mutation. Consequently, the recipient’s mutation was presumed to be de novo, allowing the donation to proceed. Notably, the donor’s zero-hour allograft biopsy revealed ultrastructural mitochondrial abnormalities but no overt light microscopic damage (i.e., no FSGS). At 22 years post-transplant, both the recipient’s graft function (serum creatinine 1.16 mg/dL, albuminuria 5.0 mg/gCr) and the donor’s remaining kidney function (serum creatinine 0.98 mg/dL, albuminuria 10.4 mg/gCr) remain excellent. Current highly sensitive genetic analysis revealed an extremely low blood heteroplasmy in the donor (0.1%) compared to 20% in the recipient, demonstrating a severe “genetic bottleneck” effect. Furthermore, the recipient’s older sister was found to have a 4% mutational load, definitively confirming maternal inheritance rather than a de novo mutation. This case represents the longest reported follow-up of a living kidney transplant from an m.3243 A > G carrier. It demonstrates that maternal carriers with extremely low heteroplasmy and no light microscopic evidence of overt renal damage on biopsy can be safe donors and provide excellent long-term graft outcomes. Precise risk stratification based on genotype and biopsy findings, rather than uniform exclusion, may expand transplant options.
2026-06-20 | Generation of a patient-derived iPSC line from a clinically diagnosed MELAS case carrying the mtDNA m.3243A > G variant.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) represents a multisystemic mitochondrial disease mainly triggered by heteroplasmic m.3243A > G mutation in mtDNA MT-TL1, the gene for tRNA^Leu(UUR). Here we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a female MELAS patient into induced pluripotent stem cells (iPSCs). This patient-specific iPSC line provides a valuable platform to investigate MELAS pathophysiology and screen therapeutic interventions targeting mitochondrial dysfunction in a genetically relevant context.
2026-06-10 | Cochlear implantation in MELAS syndrome: a systematic review of audiological outcomes, surgical considerations, and clinical implications
Abstract Purpose Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder frequently associated with sensorineural hearing loss (SNHL). Due to mitochondrial dysfunction, cochlear structures, especially the stria vascularis and outer hair cells, are susceptible to damage, causing progressive hearing impairment. Cochlear implantation (CI) offers rehabilitative potential, yet unique perioperative challenges related to anesthetic sensitivity and metabolic instability require tailored management strategies. Limited evidence exists regarding CI outcomes specifically in MELAS patients. This systematic review critically evaluates existing literature on CI efficacy, audiological outcomes, and perioperative considerations in MELAS. Methods A comprehensive systematic review following PRISMA guidelines was conducted. Databases including PubMed, Embase, Web of Science, and Scopus were searched for relevant studies reporting outcomes of CI in MELAS patients. Two independent reviewers performed article screening, data extraction, and risk-of-bias assessment. Results From 292 retrieved studies, 8 studies ( n = 10 patients) were included. Audiological outcomes consistently showed substantial improvement in speech perception tests post-CI. Standardized assessments demonstrated enhanced sentence and word recognition, alongside improved auditory-evoked potentials (ABR, MLR). Patients reported improvement in social engagement and communication. Surgical interventions were successful despite unique perioperative challenges related to MELAS pathology, including anesthesia complications and metabolic crises. However, existing studies primarily consisted of individual case reports, limiting generalizability. Conclusion Cochlear implantation is an effective rehabilitative option for patients with MELAS syndrome and severe-to-profound sensorineural hearing loss, improving speech perception and communication. Audiological outcomes and electrophysiological measures support its role in restoring auditory function in this unique population. However, given the risks of metabolic decompensation, anesthetic sensitivity, and perioperative electrolyte disturbances in MELAS, careful planning of anesthesia and surgical protocols is critical to patient safety.
2026-04-24 | iPSC generation from PBMCs of a MELAS patient for mitochondrial dysfunction studies.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a multisystemic mitochondrial disorder primarily caused by a heteroplasmic point mutation at mitochondrial DNA (mtDNA) position 3243 (m.3243A > G) in the MT-TL1 gene, which encodes mitochondrial tRNA^Leu(UUR). In this study, we report the successful reprogramming of peripheral blood mononuclear cells (PBMCs) from a male patient diagnosed with MELAS into induced pluripotent stem cells (iPSCs). This patient-specific iPSC platform enables investigation into the relationship between heteroplasmy levels and disease manifestation and provides a valuable tool for screening potential therapeutic strategies aimed at mitigating mitochondrial dysfunction in MELAS.
2026-02-09 | Case Report: Simultaneous pancreas-kidney transplantation in MELAS: first reported case with 5-year follow-up.
Mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial DNA disorder that, in severe cases, can result in insulin-dependent diabetes and end-stage renal disease (ESRD). While organ transplantation is a potential treatment, documented cases remain scarce. A 40-year-old patient with dialysis-dependent ESRD and diabetes secondary to MELAS underwent simultaneous pancreas-kidney transplantation. The perioperative and postoperative periods were uncomplicated with only targeted MELAS-specific adaptations to standard protocols. During the 5-year follow-up, the patient maintained excellent kidney allograft function and sustained insulin independence, with no need for dialysis or exogenous insulin therapy. At 5 years, creatinine was 77 µmol/L with an estimated GFR above 90 mL/min/1.73 m2, and glycated hemoglobin was 40 mmol/mol. SPK transplantation may be feasible in carefully selected patients with MELAS, ESRD, and diabetes, providing durable renal and metabolic graft function at 5 years. To our knowledge, this is the first reported SPK case in MELAS, with extended follow-up.
other
2025-05-09 | Genetic migraine disorders and the response to calcitonin gene-related peptide antagonist treatment.
Calcitonin gene-related peptide (CGRP) is a potent cerebral vasodilator and part of the trigeminal migraine cascade. Newer migraine therapies target CGRP signaling for both acute and preventative management of headache. In this series, we present two cases of genetic conditions, of which migraine is a key feature, responsive to CGRP antagonist therapy. A 31-year-old female with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and a phenotype of chronic migraine with visual aura, and a 62-year-old female with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with a phenotype of chronic migraine and side-locked headache with cranial autonomic symptoms. Each experienced a significant reduction in the frequency of their migraine attacks with monoclonal antibody treatment against CGRP. In this case series, we add to the growing body of evidence that CGRP-blocking medications are safe and effective in some heritable neurological disorders in which vasomodulation is a common underlying pathology. To our knowledge, we present the first cases of galcanezumab use in an individual with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and eptinezumab in an individual with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
2024-02-22 | Collision-Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial Transfer Ribonucleic Acids.
Ribonucleic acids (RNAs) remain challenging targets for structural biology, creating barriers to understanding their vast functions in cellular biology and fully realizing their applications in biotechnology. The inherent dynamism of RNAs creates numerous obstacles in capturing their biologically relevant higher-order structures (HOSs), and as a result, many RNA functions remain unknown. In this study, we describe the development of native ion mobility-mass spectrometry and collision-induced unfolding (CIU) for the structural characterization of a variety of RNAs. We evaluate the ability of these techniques to preserve native structural features in the gas phase across a wide range of functional RNAs. Finally, we apply these tools to study the elusive mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes-associated A3243G mutation. Our data demonstrate that our experimentally determined conditions preserve some solution-state memory of RNAs via the correlated complexity of CIU fingerprints and RNA HOS, the observation of predicted stability shifts in the control RNA samples, and the retention of predicted magnesium binding events in gas-phase RNA ions. Significant differences in collision cross section and stability are observed as a function of the A3243G mutation across a subset of the mitochondrial tRNA maturation pathway. We conclude by discussing the potential application of CIU for the development of RNA-based biotherapeutics and, more broadly, transcriptomic characterization.
2023-09-08 | Collision Induced Unfolding Reveals Disease-Associated Stability Shifts in Mitochondrial tRNAs
Ribonucleic acids (RNAs) remain challenging targets for structural biology, creating barriers to understanding their vast functions in cellular biology and fully realizing their applications in biotechnology. The inherent dynamism of RNAs creates numerous obstacles in capturing their biologically relevant higher-order structures (HOSs), and as a result, many RNA functions remain unknown. In this report, we describe the development of native ion mobility-mass spectrometry (IM-MS) and collision induced unfolding (CIU) for the structural characterization of a variety of RNAs. We evaluate the ability of these techniques to preserve native structural features into the gas-phase across a wide range of functional RNAs. Finally, we apply these tools to study the elusive mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)-associated A3243G mutation. Our data demonstrate that our experimentally determined conditions preserve some solution-state memory of RNA via the increasing complexity of CIU fingerprints by RNA HOS and the retention of predicted magnesium binding events. Relating to the role of MELAS-inducing mutations in mitochondrial trans-fer RNA (mt-tRNAs), significant differences in collision cross-section (CCS) and stability are observed as a function of the A3243G mutation across a subset of the mitochondrial transfer RNA (tRNA) maturation pathway. We conclude by discussing the potential application of CIU for the development of RNA-based biotherapeutics and, more broadly, transcriptomic characterization.
2023-09-03 | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease
In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeuUUR and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development.
2019-11-13 | Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation
Translation fidelity is crucial for prokaryotes and eukaryotic nuclear-encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error-prone and hyper-accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian-specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.
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Drug Discovery Landscape
8 orphan drug designations for MELAS.
8 orphan drug designations for MELAS.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
taurine | small molecules | FDA | — | Kalevala Therapeutics, Inc. |
Vatiquinone | small molecules | EMA | PTC Therapeutics International Limited | |
Mavodelpar sodium | small molecules | EMA | Scendea (NL) B.V. | |
2-isopropyl-3H-naphtho[1,2-d]imidazole-4,5-dione | small molecules | EMA | Pharming Technologies B.V. | |
nicotinamide riboside | small molecules | FDA | Rejuvenation Therapeutics | |
Sonlicromanol hydrochloride [KH176] | small molecules | EMA | Khondrion B.V. | |
idebenone | small molecules | FDA | Santhera Pharmaceuticals (Switzerland) Ltd. | |
5-[(E)-2-(4-hydroxyphenyl)-ethenyl] benzene-1,3 diol | small molecules | FDA | — | Sirtris Pharmaceuticals, Inc. |
“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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