RARE DISEASE
Mitochondrial myopathy
Mitochondrial myopathy
Mitochondrial myopathy
Drug discovery
4
drugs
With orphan designations
Overview
Mitochondrial myopathies are genetic disorders resulting from impaired mitochondrial oxidative phosphorylation, leading to cellular energy deficits. Primarily affecting skeletal muscle, they manifest with progressive weakness, exercise intolerance, and multiorgan involvement (e.g., CNS, cardiac, endocrine). Diagnosis relies on genetic testing, muscle biopsy (ragged-red fibers, COX-negative fibers), and elevated lactate [1][6][12][19].
Burden
High morbidity: 69% develop CNS involvement; 21% have cardiac disease (median survival post-diagnosis: 10.9 years) [2][4].
Healthcare costs average $24,023/year pre-hospitalization, rising to $33,545/year post-hospitalization [4].
Mortality correlates with multisystem progression (e.g., median age at death: 55 years) [2].
Therapies
Supportive care: Coenzyme Q10, riboflavin, and L-carnitine to enhance energy metabolism [3][17].
Emerging therapies: Nicotinamide riboside (induces mitochondrial biogenesis) [13], gene therapy (e.g., mtDNA heteroplasmy shifting) [8], and hypoxia adaptation [3].
Symptomatic management: Anticonvulsants, cardiac interventions (e.g., ICDs for arrhythmias), and physical therapy [5][12].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,219 drug discovery papers about Mitochondrial myopathy, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,219 drug discovery papers about Mitochondrial myopathy, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Incretin-Based Therapies: A Testable Hypothesis Linking Incretin Signaling, Mitochondrial Redox, and OXPHOS Efficiency.
Incretin-based obesity therapies (IBTs), especially GLP-1 receptor agonists (GLP-1 RAs), effectively treat obesity and improve comorbidities. However, their impact on energy metabolism is unclear. A recent case of acute generalized muscle weakness in a patient with mitochondrial myopathy after tirzepatide exposure raises concerns about IBTs' potential to uncouple oxidative phosphorylation (OXPHOS). Given the widespread use of IBTs, this inquiry is crucial due to potential adverse effects. A narrative literature review of evidence linking incretins and IBTs to mitochondrial physiology, bioenergetics, and OXPHOS was conducted. Early research on incretin physiology focused on insulin secretion in pancreatic β-cells. However, GLP-1 counteracts insulin signaling during excessive nutrient delivery by activating anti-inflammatory pathways associated with fasting, suggesting it mitigates the adverse effects of overfeeding. Preclinical studies show that IBTs activate thermogenic genes and uncoupling proteins. We have identified indirect evidence suggesting that IBTs may induce OXPHOS uncoupling. We propose a testable hypothesis that establishes a close relationship between the distinct effects of IBTs on weight loss and their direct reduction of oxidative stress. Should this hypothesis be validated, it would enhance our comprehension of the physiology underlying IBTs and the potential adverse effects on muscle.
2026-08-19 | Supplemental Material for: From Mitochondrial Myopathy to SLC18A3 - Related Congenital Presynaptic Myasthenic Syndrome: A Case Report
Introduction: Recognizing congenital myasthenic syndromes is essential, as appropriate medication can improve muscle weakness.Case presentation: We report on a 25-year-old male, who was diagnosed with a mitochondrial myopathy based on muscle biopsy in childhood, although genetic testing of the mitochondrial DNA did not show abnormalities. New analysis including a gene panel revealed two novel variants in the SLC18A3 gene, and characteristic electromyography findings changed his diagnosis to a congenital myasthenic syndrome. Treatment was started which significantly improved his quality of life.Conclusion: Our report underscores the importance of re-evaluating diagnoses in patient without genetic confirmation, so that treatable conditions are not overlooked.
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.
2026-08-01 | MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial function.
Bi-allelic mutations in MSTO1 are linked to clinical disease phenotypes characteristic of mitochondrial dysfunction, including ataxia and muscular dystrophy. Consistent with this, MSTO1 patient-derived fibroblasts have fragmented mitochondria and a striking loss of mtDNA. Although MSTO1 has been implicated in regulating mitochondrial fusion, the molecular function of this cytosolic protein in vertebrate cells remains unclear. Using the auxin-inducible degradation (AID) system we demonstrate that MSTO1-FLAG-AID protein is rapidly depleted to almost undetectable levels. Importantly, these cells recapitulate the fragmented mitochondrial phenotype observed in patients and thus are a valuable model of disease. Surprisingly, prior to any changes in mitochondria, we show that MSTO1-depleted cells have a significant decrease in TRiC levels, an essential cytosolic ATP-dependent chaperone required to fold diverse substrates, including actin and tubulin. We reveal that TRiC is also reduced in MSTO1 patient-derived fibroblasts, indicating that loss of TRiC may contribute to disease pathophysiology. We further demonstrate that knockdown of TRiC leads to a decrease in MSTO1 protein levels and remarkably, was sufficient to induce a fragmented mitochondrial phenotype, independent of changes in tubulin or actin. This reveals a previously unrecognized connection between TRiC and mitochondrial homeostasis. Using co-immunoprecipitation we found that MSTO1 interacts with the TRiC chaperone. We also observe accumulation of early TRiC assembly subcomplexes in the absence of MSTO1 suggesting that MSTO1 facilitates assembly of TRiC. Together, our findings identify MSTO1 as a TRiC assembly factor and connect mitochondrial defects caused by MSTO1-depletion to the loss of TRiC. MSTO1, a protein linked to myopathy and ataxia, has been thought to control mitochondrial fusion, although the molecular mechanism is unknown. Using rapid depletion of MSTO1, we found that mitochondrial fragmentation appears only after six days. Significantly, the levels of the essential cytosolic chaperonin TRiC are reduced within two days of MSTO1 depletion. Directly depleting TRiC reproduces the fragmented mitochondrial phenotype seen with loss of MSTO1, consistent with a model where mitochondrial dysfunction is a downstream consequence of impaired protein folding rather than a direct effect of MSTO1 loss. We show that MSTO1 is required for assembly of TRiC, identifying it as a long-sought assembly factor for this macromolecular protein complex.
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.
cell therapies
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.
2026-02-13 | Fusion Between Control Mesoangioblasts and mtDNA-Mutant Myotubes Preserves Myotube Morphology and Mitochondrial Network Organization.
Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study we investigated mitochondrial morphology and membrane potential in vitro in mesoangioblast-derived human myotubes harboring a pathogenic mtDNA mutation and analyzed mitochondrial behavior following fusion with healthy mesoangioblasts. Myotubes were differentiated in vitro from mesoangioblasts obtained from two mitochondrial myopathy patients, M02 (96% m.3271T>C) and M11 (73% m.3291T>C), and from a functionally healthy male control, M06 (3% m.3243A>G). On day 5 of differentiation, healthy male mesoangioblasts (mM06) were added to mutant myotube cultures to allow cell fusion. On day 11, mitochondrial morphology and membrane potential were assessed by three-dimensional live-cell imaging using spinning disk confocal microscopy with tetramethylrhodamine methyl ester (TMRM). Following live imaging, cells were fixed and subjected to Y-chromosome fluorescence in situ hybridization (FISH), enabling identification and retrospective analysis of hybrid (i.e., fused with male control mesoangioblasts) and non-hybrid (i.e., not fused with these control mesoangioblasts) myotubes within the same imaging fields. Quantitative image analysis at the level of individual myotubes revealed that, when normalized to sarcoplasmic volume, mitochondrial volume, object number, and membrane potential did not differ between mutant and control myotubes despite heteroplasmy levels exceeding 70%. Fusion of healthy mM06 mesoangioblasts did not impair myotube formation and resulted in redistribution of mitochondrial content without an increase in mitochondrial object number, consistent with integration of donor mitochondria into the existing mitochondrial network. Across conditions, mitochondrial parameters were strongly influenced by myotube size, underscoring the importance of accounting for biological variation when quantifying mitochondrial features. Together, these findings demonstrate that high mtDNA mutation loads do not necessarily alter mitochondrial morphology or membrane potential under standard in vitro differentiation conditions and provide mechanistic insight into mitochondrial behavior following mesoangioblast fusion in human myotubes. Fusion of healthy mesoangioblasts supports integration of donor mitochondria into the existing network without compromising myogenesis, consistent with mitochondrial mixing rather than replacement.
2025-07-19 | Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe: First phase 1/2 human clinical study.
Progressive myopathy and exercise intolerance significantly impair quality of life in over 50% of m.3243A>G mutation carriers, with no curative therapy currently available. We hypothesize that intra-arterial administration of autologous, mtDNA mutation-free myogenic stem cells, mesoangioblasts, can reduce mutation load, enhance oxidative phosphorylation, and improve muscle function. To test this, the tibialis anterior muscles of three m.3243A>G mutation carriers were damaged by eccentric exercise before the infusion of 50 million/kg autologous mesoangioblasts into the left anterior tibial artery. The right tibialis anterior muscle served as control. Expanded mesoangioblasts had a mutation load of <15%, although culturing increased this by 7%-15%. Infusion caused mild, transient discomfort without serious adverse events or vascular obstructions, as confirmed by angiography. Blood and muscle biopsies revealed no systemic or local inflammation at 24 h and 4 weeks post-transplantation. Biopsies of the treated muscle suggested mesoangioblast migration and early signs of regeneration. This first-in-human study demonstrates that intra-arterial administration of autologous mesoangioblasts is safe, with promising, although inconclusive, evidence for muscle regeneration and mesoangioblast homing. These findings support further investigation into the therapeutic potential of mesoangioblasts for treating myopathy in m.3243A>G mutation carriers.
2025-05-01 | Adipose-Derived Mesenchymal Stem Cell Therapy Improves Skeletal Muscle Mitochondrial Function in a Porcine Model of Peripheral Artery Disease
Introduction: Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in mitochondrial myopathy in the affected leg muscles and significant walking impairment. Previous studies using a porcine model of PAD have shown that injection of adipose-derived mesenchymal stem cells (ADMSC) around the aortic trifurcation in the pelvis improves ischemic limb hemodynamics and walking performance. However, the effect of ADMSC treatment on skeletal muscle mitochondrial function remains unknown. Hypothesis: We hypothesized that ADMSC injection around the aortic trifurcation in the pelvis improves skeletal muscle mitochondrial function in a swine model of PAD. Methods: Ten Ossabaw miniswine (age 6 months) with metabolic syndrome were used. Right hindlimb ischemia was induced at week 0 (T0) by coil occlusion of the right external iliac, superficial femoral, and popliteal arteries via carotid artery access. At week 4 (T4), ADMSC (20 x 106 cells) were isolated using stromal vascular fractionation of autologous abdominal wall fat. Using jugular vein access, a catheter with a retractable side-deploying needle was inserted in the right iliac vein. The needle was deployed to access the retroperitoneum, and ADMSC (N=5) or vehicle (N=5) were infused around the aortic trifurcation. Gastrocnemius samples from the ischemic hindlimb were obtained at T4 (before treatment) and week 8 (T8, 4 weeks after treatment) to assess mitochondrial function using high resolution respirometry. Results: ADMSC treatment significantly increased mitochondrial respiration at T8 compared to T4 in complex I (T8: 27.92 ± 1.96; T4: 20.22 ± 2.01 pmols·s-1·mg-1; p<0.05), complex II (T8: 35.71 ± 1.79; T4: 24.01 ± 2.44 pmols·s-1·mg-1; p<0.05) and complex I+II state 3 (T8: 62.75 ± 3.25; T4: 44.23 ± 4.37 pmols·s-1·mg-1; p<0.05), and state 4 (T8: 22.13 ± 1.16; T4: 16.45 ± 1.3 pmols·s-1·mg-1; p<0.05) in the ischemic hindlimbs of ADMSC-treated swine. Conclusions: Our study, using a clinically relevant porcine model of PAD, similar to humans in size, anatomy, physiology, and comorbidities, demonstrates that ADMSC therapy can effectively improve mitochondrial function in ischemic hindlimbs. These findings suggest that ADMSC may be a promising treatment for mitochondrial myopathy in patients with PAD. Funding sources: R01 AG062198, R01 AG077803, R01 HD106911, P20 GM152301, and the Nebraska Research Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2024-01-18 | The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases
Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized.
gene therapies
2026-09-30 | Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.
2026-02-13 | Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.
Myopathies represent a highly heterogeneous group of primary muscle disorders, traditionally classified based on clinical presentation and histopathological findings. Recent breakthroughs in molecular genetics, immunology, and pathophysiology have revolutionized the understanding, diagnosis, and management of these conditions. Both inherited and acquired forms of myopathy, including structural, metabolic, inflammatory, endocrine, and mitochondrial subtypes, are now recognized to arise from diverse pathogenic mechanisms such as impaired calcium handling, mitochondrial dysfunction, chronic inflammation, altered metabolism, and defective muscle regeneration. The advent of next-generation sequencing technologies has enabled more precise diagnosis of genetic forms, while the discovery of novel molecular biomarkers and immunological signatures offers promising avenues for disease monitoring and stratification across the broader spectrum. Importantly, molecular and mechanistic insights have redefined clinical classifications, allowing for better prognostic predictions and patient-tailored therapeutic approaches. Innovative treatments, including gene therapy, antisense oligonucleotide therapies, immune-modulating agents, metabolic support strategies, and targeted pharmacological interventions, are progressively translating molecular knowledge into clinical applications. However, technical limitations, biological variability, and ethical considerations continue to pose significant challenges to the implementation of precision medicine in myopathies. In this narrative review, we comprehensively discuss the latest molecular findings, their integration into clinical practice, and the emerging therapeutic strategies based on these discoveries. We also highlight current limitations and propose future research directions aimed at bridging the gap between molecular insights and effective, equitable patient care.
2026-01-04 | CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
Mitochondrial dysfunction is a hallmark of myopathies and impaired skeletal muscle differentiation. Here, we demonstrate that C1q/TNF-related protein 1 (CTRP1) is essential for maintaining mitochondrial dynamics and supporting myogenic differentiation. Loss of CTRP1 in myoblasts and in skeletal muscle-specific-knockout (CTRP1 KOΔACTA) mice led to impaired myotube formation, reduced muscle fiber cross-sectional area, and decreased muscle strength. CTRP1 deficiency also shifted the muscle fiber composition from oxidative type IIA to glycolytic type IIB fibers, indicating a compromised mitochondrial capacity. At the cellular level, CTRP1 loss resulted in elongated and disorganized mitochondria with diminished cristae density, membrane potential, and oxidative respiration. These mitochondrial abnormalities are associated with defective recruitment of dynamin-related protein 1 (DRP1), a central mediator of mitochondrial fission. Restoring CTRP1 expression or performing mitochondrial transplantation in CTRP1-KO myoblasts rescued mitochondrial function and re-established differentiation capacity. Furthermore, CTRP1 expression progressively decreased in accordance with disease severity in skeletal muscle biopsies from patients with polymyositis, dermatomyositis, and Duchenne muscular dystrophy, supporting its potential relevance to human myopathies. Together, these findings identify CTRP1 as a novel regulator of mitochondrial quality and myogenic differentiation, highlighting its potential as a therapeutic target for mitochondrial myopathies.
2025-12-25 | Transient muscle expression of mitoARCUS in mice leads to sustained reductions in pathogenic mtDNA and reduces fatigability.
Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load, which was maintained up to 42 weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.
2025-12-16 | Mitochondrial permeability transition pore (mPTP) as a target for drug delivery systems: challenges and opportunities
The mitochondrial permeability transition pore (mPTP) is a critical regulator of mitochondrial function and cellular fate, serving as both a therapeutic target and a potential barrier in drug delivery. Prolonged or inappropriate mPTP opening is implicated in various pathological conditions, including cancer, neurodegenerative diseases, and cardiovascular disorders. Several mPTP-targeted molecules such as Cyclosporin A (for cardioprotection), MitoQ (for neurodegeneration), and Elamipretide (for mitochondrial myopathy) have advanced to Phase II/III clinical trials, demonstrating improvements in mitochondrial membrane potential, ATP recovery, and reduced oxidative damage. Emerging interventions including CRISPR-mediated PPIF inhibition and exosome-mediated delivery systems further highlight the potential for personalized, tissue-specific mitochondrial therapy. In addition, we review the therapeutic applications of mPTP modulation in conditions like ischemia-reperfusion injury, neurodegeneration, and cancer, and present case studies of successful interventions. Looking ahead, emerging strategies such as precision medicine and combination therapies are poised to improve the efficacy of mPTP-targeted treatments. This review concludes with a discussion on the future directions in mPTP research and the need for a deeper understanding of its complex regulatory mechanisms.
proteins
2026-09-30 | Lightning Strikes Twice in the Same Place: Mitochondrial Myopathy and Malignant Hyperthermia-A Case Report.
Mitochondrial disease predominantly affects tissues reliant on aerobic metabolism, with an incidence of 1 in 4000 individuals and a broad spectrum of clinical presentations. Malignant hyperthermia is a pharmacogenetic disease in which a hypermetabolic reaction is triggered in malignant hyperthermia-susceptible patients by specific anesthetic agents. We present a clinical case of a fatal atypical reaction to anesthesia, where mitochondrial dysfunction was identified in the mother, and a variant in the RYR1 gene was found in the asymptomatic father and a paternal first cousin with exercise-induced rhabdomyolysis. Our report highlights that patients with complex phenotypes may present with concomitant diseases, necessitating comprehensive and often competing management priorities.
2026-09-15 | Relaxin-2: Shaping the Proteomic Landscape of Skeletal Muscle Physiology, Glucose Trafficking, and Mitochondrial Function in Rat.
Relaxin-2 is a hormone with robust beneficial effects on the heart and blood vessels and potential as a therapy for cardiovascular (CV) disease. Considering the interorgan communication between skeletal muscle and heart, and the relation between muscle quality/composition and CV events, we hypothesize that relaxin-2 may regulate skeletal muscle physiology and metabolism. We aim to evaluate the impact of relaxin-2 on the proteome of skeletal muscle from healthy Sprague-Dawley rats. Animals were treated with 0.4 mg/kg/day of serelaxin (recombinant form of human relaxin-2) or vehicle (PBS) for 2 weeks employing subcutaneous osmotic minipumps. Skeletal muscle protein identification and quantification were performed by LC-MS/MS using a Data-Independent Acquisition (DIA)-Sequential Window Acquisition of All Theoretical Fragment Ion Spectra (SWATH) method. SWATH/MS quantitative analysis identified that relaxin-2 significantly decreased 95 proteins and significantly increased 32 proteins in rat skeletal muscle when compared to control rats. From these, 34 proteins were associated with muscle function, myogenesis, muscle differentiation and/or regeneration, 20 are mitochondrial proteins (six from the complexes of the electron transport chain), and 10 proteins participate in glucose metabolism. Qualitative data-dependent workflow analysis identified 35 proteins exclusive to the skeletal muscle of the relaxin-2-treated group: eight proteins related to processes of skeletal muscle function (size, ion homeostasis or organization of caveolae structures and cytoskeleton) and myogenesis, and two proteins involved in muscle differentiation. Our work highlighted for the first time the role of relaxin-2 in crucial processes of muscle physiology and energetic metabolism, which could influence several processes involved in myopathy and CV.
2026-09-03 | Dataset related to article: BIALLELIC VARIANTS IN AK3 ASSOCIATED WITH PEO, MITOCHONDRIAL MYOPATHY AND MTDNA MULTIPLE DELETIONS
AK3 MANUSCRIPT data
2026-08-18 | Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.
2026-08-01 | Delayed Diagnosis of m.3243A>G-Related Cardiomyopathy Prompted by Echocardiography
The mitochondrial DNA m.3243A>G variant is one of the most common pathogenic mitochondrial DNA variants.1 It accounts for approximately 80% of cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and is also associated with a broad spectrum of adult mitochondrial diseases, including maternally inherited diabetes and deafness (MIDD), MELAS/MIDD overlap, and nonsyndromic multisystem phenotypes.2 Here we describe 2 patients with delayed recognition of m.3243A>G-related cardiomyopathy in whom mitochondrial disease was suspected on the basis of echocardiographic findings 20 and 32 years after the onset of diabetes mellitus, respectively.
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.
2025-02-20 | GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM. The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting. Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals. Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.
2023-12-21 | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting.
Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. However, transport vehicles are needed for intracellular, mitochondria-specific transport of oligonucleotides. Nanoparticle (NP) based vectors such as large pore mesoporous silica nanoparticles (LP) often rely on surface complexation of oligonucleotides exposing them to nucleases and limiting mitochondria targeting and controlled release ability. In this work, stable, fluorescent, hollow silica nanoparticles (HSN) that encapsulate and protect oligonucleotides in the hollow core were synthesized by a facile one-pot procedure. Both rhodamine B isothiocyanate and bis[3-(triethoxysilyl)propyl]tetrasulfide were incorporated in the HSN matrix by co-condensation to enable cell tracing, intracellular-specific degradation and controlled oligonucleotide release. We also synthesized LP as a benchmark to compare the oligonucleotide loading and release efficacy of our HSN. Mitochondria targeting was enabled by NP functionalization with cationic, lipophilic Triphenylphosphine (TPP) and, for the first time a fusogenic liposome based carrier, previously reported under the name MITO-Porter. HSN exhibited high oligonucleotide incorporation ratios and release dependent on intracellular degradation. Further, MITO-Porter capping of our NP enabled delayed, glutathione (GSH) responsive oligonucleotide release and mitochondria targeting at the same efficiency as TPP functionalized NP. Overall, our NP are promising vectors for anti-gene therapy of mtDNA disease as well as many other monogenic disorders worldwide.
2023-07-13 | Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation
Abstract The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.
2021-09-16 | Successful treatment of a patient with mitochondrial myopathy with alirocumab.
A 48-year-old man presented to our lipid clinic with statin intolerance and elevated serum creatine kinase levels, being affected by mitochondrial myopathy because of heteroplasmic mitochondrial DNA missense mutation in MTCO1 gene (m.7671T>A). He had just been treated with a coronary artery bypass 4 years before because of acute coronary syndrome, and he had consistently high levels of both low-density lipoprotein cholesterol and triglycerides. Dyslipidemia was successfully treated using 75 mg of alirocumab subcutaneously every 2 weeks, 10 mg of ezetimibe daily, 2 g of marine omega-3 fatty acids daily, and 145 mg of micronized fenofibrate every 2 days. Although muscle weakness persisted, myalgia did not reoccur and serum creatine kinase levels remained almost stable over the time.
small molecules
2026-09-24 | Incretin-Based Therapies: A Testable Hypothesis Linking Incretin Signaling, Mitochondrial Redox, and OXPHOS Efficiency.
Incretin-based obesity therapies (IBTs), especially GLP-1 receptor agonists (GLP-1 RAs), effectively treat obesity and improve comorbidities. However, their impact on energy metabolism is unclear. A recent case of acute generalized muscle weakness in a patient with mitochondrial myopathy after tirzepatide exposure raises concerns about IBTs' potential to uncouple oxidative phosphorylation (OXPHOS). Given the widespread use of IBTs, this inquiry is crucial due to potential adverse effects. A narrative literature review of evidence linking incretins and IBTs to mitochondrial physiology, bioenergetics, and OXPHOS was conducted. Early research on incretin physiology focused on insulin secretion in pancreatic β-cells. However, GLP-1 counteracts insulin signaling during excessive nutrient delivery by activating anti-inflammatory pathways associated with fasting, suggesting it mitigates the adverse effects of overfeeding. Preclinical studies show that IBTs activate thermogenic genes and uncoupling proteins. We have identified indirect evidence suggesting that IBTs may induce OXPHOS uncoupling. We propose a testable hypothesis that establishes a close relationship between the distinct effects of IBTs on weight loss and their direct reduction of oxidative stress. Should this hypothesis be validated, it would enhance our comprehension of the physiology underlying IBTs and the potential adverse effects on muscle.
2026-08-19 | Supplemental Material for: From Mitochondrial Myopathy to SLC18A3 - Related Congenital Presynaptic Myasthenic Syndrome: A Case Report
Introduction: Recognizing congenital myasthenic syndromes is essential, as appropriate medication can improve muscle weakness.Case presentation: We report on a 25-year-old male, who was diagnosed with a mitochondrial myopathy based on muscle biopsy in childhood, although genetic testing of the mitochondrial DNA did not show abnormalities. New analysis including a gene panel revealed two novel variants in the SLC18A3 gene, and characteristic electromyography findings changed his diagnosis to a congenital myasthenic syndrome. Treatment was started which significantly improved his quality of life.Conclusion: Our report underscores the importance of re-evaluating diagnoses in patient without genetic confirmation, so that treatable conditions are not overlooked.
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.
2026-08-01 | MSTO1 functions as a TRiC assembly factor linking cytosolic proteostasis to mitochondrial function.
Bi-allelic mutations in MSTO1 are linked to clinical disease phenotypes characteristic of mitochondrial dysfunction, including ataxia and muscular dystrophy. Consistent with this, MSTO1 patient-derived fibroblasts have fragmented mitochondria and a striking loss of mtDNA. Although MSTO1 has been implicated in regulating mitochondrial fusion, the molecular function of this cytosolic protein in vertebrate cells remains unclear. Using the auxin-inducible degradation (AID) system we demonstrate that MSTO1-FLAG-AID protein is rapidly depleted to almost undetectable levels. Importantly, these cells recapitulate the fragmented mitochondrial phenotype observed in patients and thus are a valuable model of disease. Surprisingly, prior to any changes in mitochondria, we show that MSTO1-depleted cells have a significant decrease in TRiC levels, an essential cytosolic ATP-dependent chaperone required to fold diverse substrates, including actin and tubulin. We reveal that TRiC is also reduced in MSTO1 patient-derived fibroblasts, indicating that loss of TRiC may contribute to disease pathophysiology. We further demonstrate that knockdown of TRiC leads to a decrease in MSTO1 protein levels and remarkably, was sufficient to induce a fragmented mitochondrial phenotype, independent of changes in tubulin or actin. This reveals a previously unrecognized connection between TRiC and mitochondrial homeostasis. Using co-immunoprecipitation we found that MSTO1 interacts with the TRiC chaperone. We also observe accumulation of early TRiC assembly subcomplexes in the absence of MSTO1 suggesting that MSTO1 facilitates assembly of TRiC. Together, our findings identify MSTO1 as a TRiC assembly factor and connect mitochondrial defects caused by MSTO1-depletion to the loss of TRiC. MSTO1, a protein linked to myopathy and ataxia, has been thought to control mitochondrial fusion, although the molecular mechanism is unknown. Using rapid depletion of MSTO1, we found that mitochondrial fragmentation appears only after six days. Significantly, the levels of the essential cytosolic chaperonin TRiC are reduced within two days of MSTO1 depletion. Directly depleting TRiC reproduces the fragmented mitochondrial phenotype seen with loss of MSTO1, consistent with a model where mitochondrial dysfunction is a downstream consequence of impaired protein folding rather than a direct effect of MSTO1 loss. We show that MSTO1 is required for assembly of TRiC, identifying it as a long-sought assembly factor for this macromolecular protein complex.
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.
cell therapies
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.
2026-02-13 | Fusion Between Control Mesoangioblasts and mtDNA-Mutant Myotubes Preserves Myotube Morphology and Mitochondrial Network Organization.
Mitochondria are the energy factories of a cell and mitochondrial morphology, quantity, membrane potential, and DNA copy number can change depending on metabolic requirements and/or genetic defects. Different mutations in mitochondrial DNA might affect mitochondrial morphology and membrane potential differently. In this study we investigated mitochondrial morphology and membrane potential in vitro in mesoangioblast-derived human myotubes harboring a pathogenic mtDNA mutation and analyzed mitochondrial behavior following fusion with healthy mesoangioblasts. Myotubes were differentiated in vitro from mesoangioblasts obtained from two mitochondrial myopathy patients, M02 (96% m.3271T>C) and M11 (73% m.3291T>C), and from a functionally healthy male control, M06 (3% m.3243A>G). On day 5 of differentiation, healthy male mesoangioblasts (mM06) were added to mutant myotube cultures to allow cell fusion. On day 11, mitochondrial morphology and membrane potential were assessed by three-dimensional live-cell imaging using spinning disk confocal microscopy with tetramethylrhodamine methyl ester (TMRM). Following live imaging, cells were fixed and subjected to Y-chromosome fluorescence in situ hybridization (FISH), enabling identification and retrospective analysis of hybrid (i.e., fused with male control mesoangioblasts) and non-hybrid (i.e., not fused with these control mesoangioblasts) myotubes within the same imaging fields. Quantitative image analysis at the level of individual myotubes revealed that, when normalized to sarcoplasmic volume, mitochondrial volume, object number, and membrane potential did not differ between mutant and control myotubes despite heteroplasmy levels exceeding 70%. Fusion of healthy mM06 mesoangioblasts did not impair myotube formation and resulted in redistribution of mitochondrial content without an increase in mitochondrial object number, consistent with integration of donor mitochondria into the existing mitochondrial network. Across conditions, mitochondrial parameters were strongly influenced by myotube size, underscoring the importance of accounting for biological variation when quantifying mitochondrial features. Together, these findings demonstrate that high mtDNA mutation loads do not necessarily alter mitochondrial morphology or membrane potential under standard in vitro differentiation conditions and provide mechanistic insight into mitochondrial behavior following mesoangioblast fusion in human myotubes. Fusion of healthy mesoangioblasts supports integration of donor mitochondria into the existing network without compromising myogenesis, consistent with mitochondrial mixing rather than replacement.
2025-07-19 | Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe: First phase 1/2 human clinical study.
Progressive myopathy and exercise intolerance significantly impair quality of life in over 50% of m.3243A>G mutation carriers, with no curative therapy currently available. We hypothesize that intra-arterial administration of autologous, mtDNA mutation-free myogenic stem cells, mesoangioblasts, can reduce mutation load, enhance oxidative phosphorylation, and improve muscle function. To test this, the tibialis anterior muscles of three m.3243A>G mutation carriers were damaged by eccentric exercise before the infusion of 50 million/kg autologous mesoangioblasts into the left anterior tibial artery. The right tibialis anterior muscle served as control. Expanded mesoangioblasts had a mutation load of <15%, although culturing increased this by 7%-15%. Infusion caused mild, transient discomfort without serious adverse events or vascular obstructions, as confirmed by angiography. Blood and muscle biopsies revealed no systemic or local inflammation at 24 h and 4 weeks post-transplantation. Biopsies of the treated muscle suggested mesoangioblast migration and early signs of regeneration. This first-in-human study demonstrates that intra-arterial administration of autologous mesoangioblasts is safe, with promising, although inconclusive, evidence for muscle regeneration and mesoangioblast homing. These findings support further investigation into the therapeutic potential of mesoangioblasts for treating myopathy in m.3243A>G mutation carriers.
2025-05-01 | Adipose-Derived Mesenchymal Stem Cell Therapy Improves Skeletal Muscle Mitochondrial Function in a Porcine Model of Peripheral Artery Disease
Introduction: Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in mitochondrial myopathy in the affected leg muscles and significant walking impairment. Previous studies using a porcine model of PAD have shown that injection of adipose-derived mesenchymal stem cells (ADMSC) around the aortic trifurcation in the pelvis improves ischemic limb hemodynamics and walking performance. However, the effect of ADMSC treatment on skeletal muscle mitochondrial function remains unknown. Hypothesis: We hypothesized that ADMSC injection around the aortic trifurcation in the pelvis improves skeletal muscle mitochondrial function in a swine model of PAD. Methods: Ten Ossabaw miniswine (age 6 months) with metabolic syndrome were used. Right hindlimb ischemia was induced at week 0 (T0) by coil occlusion of the right external iliac, superficial femoral, and popliteal arteries via carotid artery access. At week 4 (T4), ADMSC (20 x 106 cells) were isolated using stromal vascular fractionation of autologous abdominal wall fat. Using jugular vein access, a catheter with a retractable side-deploying needle was inserted in the right iliac vein. The needle was deployed to access the retroperitoneum, and ADMSC (N=5) or vehicle (N=5) were infused around the aortic trifurcation. Gastrocnemius samples from the ischemic hindlimb were obtained at T4 (before treatment) and week 8 (T8, 4 weeks after treatment) to assess mitochondrial function using high resolution respirometry. Results: ADMSC treatment significantly increased mitochondrial respiration at T8 compared to T4 in complex I (T8: 27.92 ± 1.96; T4: 20.22 ± 2.01 pmols·s-1·mg-1; p<0.05), complex II (T8: 35.71 ± 1.79; T4: 24.01 ± 2.44 pmols·s-1·mg-1; p<0.05) and complex I+II state 3 (T8: 62.75 ± 3.25; T4: 44.23 ± 4.37 pmols·s-1·mg-1; p<0.05), and state 4 (T8: 22.13 ± 1.16; T4: 16.45 ± 1.3 pmols·s-1·mg-1; p<0.05) in the ischemic hindlimbs of ADMSC-treated swine. Conclusions: Our study, using a clinically relevant porcine model of PAD, similar to humans in size, anatomy, physiology, and comorbidities, demonstrates that ADMSC therapy can effectively improve mitochondrial function in ischemic hindlimbs. These findings suggest that ADMSC may be a promising treatment for mitochondrial myopathy in patients with PAD. Funding sources: R01 AG062198, R01 AG077803, R01 HD106911, P20 GM152301, and the Nebraska Research Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2024-01-18 | The Research Progress of Mitochondrial Transplantation in the Treatment of Mitochondrial Defective Diseases
Mitochondria are double-membrane organelles that are involved in energy production, apoptosis, and signaling in eukaryotic cells. Several studies conducted over the past decades have correlated mitochondrial dysfunction with various diseases, including cerebral ischemia, myocardial ischemia-reperfusion, and cancer. Mitochondrial transplantation entails importing intact mitochondria from healthy tissues into diseased tissues with damaged mitochondria to rescue the injured cells. In this review, the different mitochondrial transplantation techniques and their clinical applications have been discussed. In addition, the challenges and future directions pertaining to mitochondrial transplantation and its potential in the treatment of diseases with defective mitochondria have been summarized.
gene therapies
2026-09-30 | Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.
2026-02-13 | Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.
Myopathies represent a highly heterogeneous group of primary muscle disorders, traditionally classified based on clinical presentation and histopathological findings. Recent breakthroughs in molecular genetics, immunology, and pathophysiology have revolutionized the understanding, diagnosis, and management of these conditions. Both inherited and acquired forms of myopathy, including structural, metabolic, inflammatory, endocrine, and mitochondrial subtypes, are now recognized to arise from diverse pathogenic mechanisms such as impaired calcium handling, mitochondrial dysfunction, chronic inflammation, altered metabolism, and defective muscle regeneration. The advent of next-generation sequencing technologies has enabled more precise diagnosis of genetic forms, while the discovery of novel molecular biomarkers and immunological signatures offers promising avenues for disease monitoring and stratification across the broader spectrum. Importantly, molecular and mechanistic insights have redefined clinical classifications, allowing for better prognostic predictions and patient-tailored therapeutic approaches. Innovative treatments, including gene therapy, antisense oligonucleotide therapies, immune-modulating agents, metabolic support strategies, and targeted pharmacological interventions, are progressively translating molecular knowledge into clinical applications. However, technical limitations, biological variability, and ethical considerations continue to pose significant challenges to the implementation of precision medicine in myopathies. In this narrative review, we comprehensively discuss the latest molecular findings, their integration into clinical practice, and the emerging therapeutic strategies based on these discoveries. We also highlight current limitations and propose future research directions aimed at bridging the gap between molecular insights and effective, equitable patient care.
2026-01-04 | CTRP1 regulates skeletal muscle differentiation through quality control of mitochondrial dynamics and function.
Mitochondrial dysfunction is a hallmark of myopathies and impaired skeletal muscle differentiation. Here, we demonstrate that C1q/TNF-related protein 1 (CTRP1) is essential for maintaining mitochondrial dynamics and supporting myogenic differentiation. Loss of CTRP1 in myoblasts and in skeletal muscle-specific-knockout (CTRP1 KOΔACTA) mice led to impaired myotube formation, reduced muscle fiber cross-sectional area, and decreased muscle strength. CTRP1 deficiency also shifted the muscle fiber composition from oxidative type IIA to glycolytic type IIB fibers, indicating a compromised mitochondrial capacity. At the cellular level, CTRP1 loss resulted in elongated and disorganized mitochondria with diminished cristae density, membrane potential, and oxidative respiration. These mitochondrial abnormalities are associated with defective recruitment of dynamin-related protein 1 (DRP1), a central mediator of mitochondrial fission. Restoring CTRP1 expression or performing mitochondrial transplantation in CTRP1-KO myoblasts rescued mitochondrial function and re-established differentiation capacity. Furthermore, CTRP1 expression progressively decreased in accordance with disease severity in skeletal muscle biopsies from patients with polymyositis, dermatomyositis, and Duchenne muscular dystrophy, supporting its potential relevance to human myopathies. Together, these findings identify CTRP1 as a novel regulator of mitochondrial quality and myogenic differentiation, highlighting its potential as a therapeutic target for mitochondrial myopathies.
2025-12-25 | Transient muscle expression of mitoARCUS in mice leads to sustained reductions in pathogenic mtDNA and reduces fatigability.
Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load, which was maintained up to 42 weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.
2025-12-16 | Mitochondrial permeability transition pore (mPTP) as a target for drug delivery systems: challenges and opportunities
The mitochondrial permeability transition pore (mPTP) is a critical regulator of mitochondrial function and cellular fate, serving as both a therapeutic target and a potential barrier in drug delivery. Prolonged or inappropriate mPTP opening is implicated in various pathological conditions, including cancer, neurodegenerative diseases, and cardiovascular disorders. Several mPTP-targeted molecules such as Cyclosporin A (for cardioprotection), MitoQ (for neurodegeneration), and Elamipretide (for mitochondrial myopathy) have advanced to Phase II/III clinical trials, demonstrating improvements in mitochondrial membrane potential, ATP recovery, and reduced oxidative damage. Emerging interventions including CRISPR-mediated PPIF inhibition and exosome-mediated delivery systems further highlight the potential for personalized, tissue-specific mitochondrial therapy. In addition, we review the therapeutic applications of mPTP modulation in conditions like ischemia-reperfusion injury, neurodegeneration, and cancer, and present case studies of successful interventions. Looking ahead, emerging strategies such as precision medicine and combination therapies are poised to improve the efficacy of mPTP-targeted treatments. This review concludes with a discussion on the future directions in mPTP research and the need for a deeper understanding of its complex regulatory mechanisms.
proteins
2026-09-30 | Lightning Strikes Twice in the Same Place: Mitochondrial Myopathy and Malignant Hyperthermia-A Case Report.
Mitochondrial disease predominantly affects tissues reliant on aerobic metabolism, with an incidence of 1 in 4000 individuals and a broad spectrum of clinical presentations. Malignant hyperthermia is a pharmacogenetic disease in which a hypermetabolic reaction is triggered in malignant hyperthermia-susceptible patients by specific anesthetic agents. We present a clinical case of a fatal atypical reaction to anesthesia, where mitochondrial dysfunction was identified in the mother, and a variant in the RYR1 gene was found in the asymptomatic father and a paternal first cousin with exercise-induced rhabdomyolysis. Our report highlights that patients with complex phenotypes may present with concomitant diseases, necessitating comprehensive and often competing management priorities.
2026-09-15 | Relaxin-2: Shaping the Proteomic Landscape of Skeletal Muscle Physiology, Glucose Trafficking, and Mitochondrial Function in Rat.
Relaxin-2 is a hormone with robust beneficial effects on the heart and blood vessels and potential as a therapy for cardiovascular (CV) disease. Considering the interorgan communication between skeletal muscle and heart, and the relation between muscle quality/composition and CV events, we hypothesize that relaxin-2 may regulate skeletal muscle physiology and metabolism. We aim to evaluate the impact of relaxin-2 on the proteome of skeletal muscle from healthy Sprague-Dawley rats. Animals were treated with 0.4 mg/kg/day of serelaxin (recombinant form of human relaxin-2) or vehicle (PBS) for 2 weeks employing subcutaneous osmotic minipumps. Skeletal muscle protein identification and quantification were performed by LC-MS/MS using a Data-Independent Acquisition (DIA)-Sequential Window Acquisition of All Theoretical Fragment Ion Spectra (SWATH) method. SWATH/MS quantitative analysis identified that relaxin-2 significantly decreased 95 proteins and significantly increased 32 proteins in rat skeletal muscle when compared to control rats. From these, 34 proteins were associated with muscle function, myogenesis, muscle differentiation and/or regeneration, 20 are mitochondrial proteins (six from the complexes of the electron transport chain), and 10 proteins participate in glucose metabolism. Qualitative data-dependent workflow analysis identified 35 proteins exclusive to the skeletal muscle of the relaxin-2-treated group: eight proteins related to processes of skeletal muscle function (size, ion homeostasis or organization of caveolae structures and cytoskeleton) and myogenesis, and two proteins involved in muscle differentiation. Our work highlighted for the first time the role of relaxin-2 in crucial processes of muscle physiology and energetic metabolism, which could influence several processes involved in myopathy and CV.
2026-09-03 | Dataset related to article: BIALLELIC VARIANTS IN AK3 ASSOCIATED WITH PEO, MITOCHONDRIAL MYOPATHY AND MTDNA MULTIPLE DELETIONS
AK3 MANUSCRIPT data
2026-08-18 | Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.
2026-08-01 | Delayed Diagnosis of m.3243A>G-Related Cardiomyopathy Prompted by Echocardiography
The mitochondrial DNA m.3243A>G variant is one of the most common pathogenic mitochondrial DNA variants.1 It accounts for approximately 80% of cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and is also associated with a broad spectrum of adult mitochondrial diseases, including maternally inherited diabetes and deafness (MIDD), MELAS/MIDD overlap, and nonsyndromic multisystem phenotypes.2 Here we describe 2 patients with delayed recognition of m.3243A>G-related cardiomyopathy in whom mitochondrial disease was suspected on the basis of echocardiographic findings 20 and 32 years after the onset of diabetes mellitus, respectively.
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.
2025-02-20 | GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy.
Primary mitochondrial myopathies (PMMs) are disorders caused by mutations in genes encoding mitochondrial proteins and proteins involved in mitochondrial function. PMMs are characterized by loss of muscle mass and strength as well as impaired exercise capacity. Growth/Differentiation Factor 15 (GDF15) was reported to be highly elevated in PMMs and cancer cachexia. Previous studies have shown that GDF15 neutralization is effective in improving skeletal muscle mass and function in cancer cachexia. It remains to be determined if the inhibition of GDF15 could be beneficial for PMMs. The purpose of the present study is to assess whether treatment with a GDF15 neutralizing antibody can alleviate muscle atrophy and physical performance impairment in a mouse model of PMM. The effects of GDF15 neutralization on PMM were assessed using PolgD257A/D257A (POLG) mice. These mice express a proofreading-deficient version of the mitochondrial DNA polymerase gamma, leading to an increased rate of mutations in mitochondrial DNA (mtDNA). These animals display increased circulating GDF15 levels, reduced muscle mass and function, exercise intolerance, and premature aging. Starting at 9 months of age, the mice were treated with an anti-GDF15 antibody (mAB2) once per week for 12 weeks. Body weight, food intake, body composition, and muscle mass were assessed. Muscle function and exercise capacity were evaluated using in vivo concentric max force stimulation assays, forced treadmill running and voluntary home-cage wheel running. Mechanistic investigations were performed via muscle histology, bulk transcriptomic analysis, RT-qPCR and western blotting. Anti-GDF15 antibody treatment ameliorated the metabolic phenotypes of the POLG animals, improving body weight (+13% ± 8%, p < 0.0001), lean mass (+13% ± 15%, p < 0.001) and muscle mass (+35% ± 24%, p < 0.001). Additionally, the treatment improved skeletal muscle max force production (+35% ± 43%, p < 0.001) and exercise performance, including treadmill (+40% ± 29%, p < 0.05) and voluntary wheel running (+320% ± 19%, p < 0.05). Mechanistically, the beneficial effects of GDF15 neutralization are linked to the reversal of the transcriptional dysregulation in genes involved in autophagy and proteasome signalling. The treatment also appears to dampen glucocorticoid signalling by suppressing circulating corticosterone levels in the POLG animals. Our findings highlight the potential of GDF15 neutralization with a monoclonal antibody as a therapeutic avenue to enhance physical performance and mitigate adverse clinical outcomes in patients with PMM.
2023-12-21 | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting.
Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. However, transport vehicles are needed for intracellular, mitochondria-specific transport of oligonucleotides. Nanoparticle (NP) based vectors such as large pore mesoporous silica nanoparticles (LP) often rely on surface complexation of oligonucleotides exposing them to nucleases and limiting mitochondria targeting and controlled release ability. In this work, stable, fluorescent, hollow silica nanoparticles (HSN) that encapsulate and protect oligonucleotides in the hollow core were synthesized by a facile one-pot procedure. Both rhodamine B isothiocyanate and bis[3-(triethoxysilyl)propyl]tetrasulfide were incorporated in the HSN matrix by co-condensation to enable cell tracing, intracellular-specific degradation and controlled oligonucleotide release. We also synthesized LP as a benchmark to compare the oligonucleotide loading and release efficacy of our HSN. Mitochondria targeting was enabled by NP functionalization with cationic, lipophilic Triphenylphosphine (TPP) and, for the first time a fusogenic liposome based carrier, previously reported under the name MITO-Porter. HSN exhibited high oligonucleotide incorporation ratios and release dependent on intracellular degradation. Further, MITO-Porter capping of our NP enabled delayed, glutathione (GSH) responsive oligonucleotide release and mitochondria targeting at the same efficiency as TPP functionalized NP. Overall, our NP are promising vectors for anti-gene therapy of mtDNA disease as well as many other monogenic disorders worldwide.
2023-07-13 | Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation
Abstract The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.
2021-09-16 | Successful treatment of a patient with mitochondrial myopathy with alirocumab.
A 48-year-old man presented to our lipid clinic with statin intolerance and elevated serum creatine kinase levels, being affected by mitochondrial myopathy because of heteroplasmic mitochondrial DNA missense mutation in MTCO1 gene (m.7671T>A). He had just been treated with a coronary artery bypass 4 years before because of acute coronary syndrome, and he had consistently high levels of both low-density lipoprotein cholesterol and triglycerides. Dyslipidemia was successfully treated using 75 mg of alirocumab subcutaneously every 2 weeks, 10 mg of ezetimibe daily, 2 g of marine omega-3 fatty acids daily, and 145 mg of micronized fenofibrate every 2 days. Although muscle weakness persisted, myalgia did not reoccur and serum creatine kinase levels remained almost stable over the time.
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Drug Discovery Landscape
4 orphan drug designations for Mitochondrial myopathy.
4 orphan drug designations for Mitochondrial myopathy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
2-(1H-imidazol-1-yl)-N-(2-(2-methoxyethoxy) pyrimidin-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide | small molecules | FDA | — | Immunophage Biotech (Shanghai) Co., Ltd. |
Sodium (4-{(E)-3-(4-fluorophenyl)-3-[4-(3-morpholin-4-yl-prop-1ynyl)phenyl]allyloxy}-2-methylphenoxy)acetate | small molecules | FDA | Reneo Pharmaceuticals Inc. | |
elamipretide | peptides | FDA | Stealth BioTherapeutics | |
Levocarnitine | small molecules | FDA | — | Leadiant Biosciences, 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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