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
1,207 drug discovery papers about Mitochondrial myopathy, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,207 drug discovery papers about Mitochondrial myopathy, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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 | 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.
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.
2026-07-23 | Total Intravenous Anesthesia With Remimazolam and Remifentanil for Intraoperative Care of a Child With Venezuelan Heritage, at Risk for a Mitochondrial Disorder.
Recent clinical communications have alerted healthcare providers to potential concerns related to a previously undiagnosed disorder of mitochondrial function in children with maternal Venezuelan heritage. These patients have developed severe neurological damage following the administration of an apparently uneventful anesthetic that included the volatile anesthetic agent, sevoflurane. Subsequent analysis of family members and patients has identified a point mutation of the NADH dehydrogenase 4 (ND4) gene (mtND4 m.11232T>C), a subunit of complex I of the mitochondrial electron transport chain. Current recommendations include avoidance of volatile anesthetic agents and propofol. We present a 6-year-old child with Venezuelan heritage who presented for anesthetic care for reduction and percutaneous pinning of a supracondylar fracture. Total intravenous anesthesia (TIVA) was provided with remimazolam and remifentanil as the primary agents. Information regarding the current investigation of this novel mitochondrial defect is presented, options for anesthetic care reviewed, and the novel use of remimazolam and remifentanil as the primary agents for TIVA discussed.
2026-07-16 | Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.
Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 ( MICU1 ), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1 , classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1 -related myopathy.
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 | 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.
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.
2026-07-23 | Total Intravenous Anesthesia With Remimazolam and Remifentanil for Intraoperative Care of a Child With Venezuelan Heritage, at Risk for a Mitochondrial Disorder.
Recent clinical communications have alerted healthcare providers to potential concerns related to a previously undiagnosed disorder of mitochondrial function in children with maternal Venezuelan heritage. These patients have developed severe neurological damage following the administration of an apparently uneventful anesthetic that included the volatile anesthetic agent, sevoflurane. Subsequent analysis of family members and patients has identified a point mutation of the NADH dehydrogenase 4 (ND4) gene (mtND4 m.11232T>C), a subunit of complex I of the mitochondrial electron transport chain. Current recommendations include avoidance of volatile anesthetic agents and propofol. We present a 6-year-old child with Venezuelan heritage who presented for anesthetic care for reduction and percutaneous pinning of a supracondylar fracture. Total intravenous anesthesia (TIVA) was provided with remimazolam and remifentanil as the primary agents. Information regarding the current investigation of this novel mitochondrial defect is presented, options for anesthetic care reviewed, and the novel use of remimazolam and remifentanil as the primary agents for TIVA discussed.
2026-07-16 | Novel Homozygous Mitochondrial Calcium Uptake Protein 1 Variant (c.38T>C, p.Leu13Pro) in a 7-year-old Girl with Congenital Ptosis and Proximal Myopathy: Expanding the Phenotypic Spectrum.
Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 ( MICU1 ), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1 , classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1 -related myopathy.
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Drug Discovery Landscape
4 orphan drug designations for Mitochondrial myopathy.
4 orphan drug designations for Mitochondrial myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2-(1H-imidazol-1-yl)-N-(2-(2-methoxyethoxy) pyrimidin-5-yl)-6-(trifluoromethyl) pyrimidine-4-carboxamide | small molecules | FDA | 2024-08-26 | — | 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 | 2020-06-02 | — | Reneo Pharmaceuticals Inc. |
elamipretide | peptides | FDA | 2017-09-05 | — | Stealth BioTherapeutics |
Levocarnitine | small molecules | FDA | 1997-04-07 | — | Leadiant Biosciences, Inc. |
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