Mitochondrial disorders …

Neuromuscular Disorders

Updated 01.16.2026
Released 02.04.2011
Expires For CME 01.16.2029

Mitochondrial disorders

Authors: Georgette Dib MD, Miriam Bekhit MD

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Editor: Nicholas E Johnson MD MSCI FAAN

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Mitochondrial disorders

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Introduction

Overview

Mitochondrial diseases represent one of the most clinically and genetically diverse groups of neurologic disorders. Rapid advances in next-generation sequencing and multi-omic technologies have transformed the diagnostic landscape, enabling earlier detection of pathogenic variants and clearer genotype–phenotype correlations. Recent discoveries have expanded the understanding of how defects in oxidative phosphorylation, mitochondrial dynamics, and organelle quality control contribute to disease. At the same time, emerging targeted therapies, including novel small-molecule approaches and early gene-based strategies, are beginning to reshape the treatment horizon. This overview highlights key developments in diagnosis and management as the field moves toward increasingly precise therapeutic strategies.

Key points

	• Mitochondrial dysfunction can affect any high-energy organ, including the brain, heart, kidney, GI tract, retina, and muscle.
	• Over 350 to 400 genes, mainly nuclear-encoded, have been implicated, with better genotype–phenotype correlations and heteroplasmy detection-enhancing diagnosis, counseling, and mechanistic understanding.
	• Therapeutic advances include FDA-approved agents (elamipretide, idebenone), emerging small molecule and gene-based strategies, multidisciplinary management, and reproductive technologies, such as mitochondrial replacement therapy.

Description

General overview. Mitochondrial diseases represent one of the most clinically and genetically heterogeneous groups of human disorders, arising from pathogenic variants in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that disrupt oxidative phosphorylation and other critical mitochondrial pathways. These conditions rank among the most common inherited metabolic disorders, with an overall lifetime risk of approximately one in 1500 (43; 05). Advances in next-generation sequencing have largely replaced muscle biopsy with minimally invasive blood sampling, enabling unbiased genetic diagnosis. Whole-exome and whole-genome sequencing have doubled the number of recognized disease genes, now exceeding 350 to 400, and significantly increased diagnostic yield (03; 32; 54).

Clinical manifestations are highly variable, reflecting the ubiquitous role of mitochondria in energy production. High-energy tissues, including the brain, sensory epithelia, extraocular muscles, cardiac muscle, and skeletal muscle, are most affected. Common features include seizures, stroke-like episodes, hearing loss, retinopathy, external ophthalmoparesis, exercise intolerance, and diabetes mellitus. The presence of two or more such features should prompt evaluation for a mitochondrial disorder. Disease severity ranges from severe childhood-onset conditions to milder adult-onset presentations (43).

Pathogenic mechanisms extend beyond primary oxidative phosphorylation defects to include mtDNA depletion or multiple deletions, disrupted NAD⁺/NADH ratios, and abnormalities in mitochondrial dynamics, including biogenesis and mitophagy. These insights have guided the development of targeted therapeutic strategies (54; 01).

Mitochondrial disorders are classified using clinical, biochemical, and molecular approaches. Clinical/syndromic classification groups patients by recognizable syndromes, such as MELAS, MERRF, Leber hereditary optic neuropathy, Kearns-Sayre, and Leigh syndrome, though many patients present with overlapping or atypical phenotypes (30; 43; 54). Biochemical classification relies on respiratory chain deficiencies or other metabolic abnormalities, but results can be limited by tissue availability and artifacts, and some genetically confirmed patients show normal biochemistry (03; 32; 01). Molecular/genetic classification, increasingly favored, categorizes disorders by underlying gene defect and function, including defects in respiratory chain subunits, assembly factors, mtDNA maintenance, translation, mitochondrial dynamics, or other functions, such as cofactor metabolism (30; 01; 14; 05). This approach enables definitive diagnosis, genetic counseling, and genotype-phenotype correlation, though current practice often integrates all three classification strategies (54; 05).

Mitochondria, remnants of protobacteria according to the endosymbiotic hypothesis, are the primary source of energy for human tissues. They host not only oxidative phosphorylation and the electron transport chain but also metabolic pathways, including the pyruvate dehydrogenase complex, amino acid catabolism, the carnitine cycle, beta-oxidation, and the tricarboxylic acid (Krebs) cycle (60).

Although defects across any of these mitochondrial pathways technically constitute mitochondrial disease, the term “mitochondrial encephalomyopathy” is most often used to describe disorders caused by respiratory chain dysfunction (19; 16). The respiratory chain represents the “business end” of oxidative metabolism, where ATP production occurs. Reducing equivalents generated by the Krebs cycle and beta-oxidation are transferred through a series of protein complexes in the inner mitochondrial membrane that make up the electron transport chain. This chain consists of four multimeric complexes (I–IV) and two mobile electron carriers—coenzyme Q10 (ubiquinone) and cytochrome c.

Electron transfer through these complexes drives proton extrusion from the mitochondrial matrix into the intermembrane space, generating an electrochemical gradient. Complex V (ATP synthase) then harnesses this gradient to synthesize ATP through oxidative phosphorylation. Disruption at any step of this process impairs cellular energy production and underlies the pathophysiology of respiratory chain–related mitochondrial encephalomyopathies.

A defining feature of the respiratory chain is its dual genetic control: mitochondrial DNA (mtDNA) encodes 13 of the approximately 89 protein subunits that constitute the oxidative phosphorylation system, whereas nuclear DNA (nDNA) encodes all remaining components. Notably, complex II (succinate dehydrogenase, which also participates in the TCA cycle), coenzyme Q10, and cytochrome c are encoded exclusively by nDNA. In contrast, complexes I, III, IV, and V contain essential mtDNA-encoded subunits: seven for complex I (ND1, ND2, ND3, ND4, ND4L, ND5, ND6), one for complex III (cytochrome b), three for complex IV (COX I, COX II, COX III), and two for complex V (ATPase 6, ATPase 8) (19; 16).

History. Initially, mitochondrial disorders were described by symptoms, and the first were mitochondrial myopathies (affecting muscles). Mitochondrial myopathies were described in the early 1960s when systematic ultrastructural and histochemical studies revealed excessive proliferation of normal- or abnormal-looking mitochondria in muscle of patients with weakness or exercise intolerance (69; 70). Because, with the modified Gomori trichrome stain, the areas of mitochondrial accumulation appeared crimson, the abnormal fibers were dubbed “ragged-red fibers” (24) and came to be considered the pathological hallmark of mitochondrial disease.

However, it soon became apparent that in many patients with ragged-red fibers, the myopathy is associated with symptoms and signs of brain involvement, and the term “mitochondrial encephalomyopathies” was introduced. It also became clear that the lack of ragged-red fibers in the biopsy does not exclude a mitochondrial etiology, as exemplified by Leigh syndrome, an encephalopathy of infancy or childhood invariably due to mitochondrial dysfunction but rarely accompanied by ragged-red fibers.

Through the 1970s and 1980s, abnormalities of oxidative phosphorylation were identified (18), so this was the assay often done. Multisystem disorders such as Kearns-Sayre (limb weakness, progressive ataxia, and ophthalmologic abnormalities) and Leigh syndrome (brain MRI findings consistent with encephalopathy) were associated with mitochondrial disease. In the late 1970s, Koeningsberger described mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as myoclonic epilepsy with ragged red fibers (MERRF) (45). Once mitochondrial DNA was characterized in 1988 (34), variations were quickly associated with diseases that had been described. However, not all patients with clear mitochondrial disease (by symptoms or respiratory chain enzyme assays) had abnormal mtDNA, and with the advent of nuclear DNA sequencing, more and more nuclear genes were associated with mitochondrial disease (09). The list of nuclear genes that cause mitochondrial disease continues to expand.

mtDNA. Human mtDNA is a 16,569-kb circular, double-stranded molecule containing 37 genes: two rRNA genes, 22 tRNA genes, and 13 structural genes encoding the respiratory chain subunits listed above.

In the course of evolution, mtDNA has lost much of its original autonomy and now depends heavily on the nuclear genome to produce factors needed for mtDNA integrity; transcription, translation, and replication (“maintenance”); inner membrane integrity; and mitochondrial dynamics (16). Mitochondrial disease can be inherited through the human mitochondrial DNA (mtDNA), which is inherited through the maternal line because it is a circular double-stranded molecule. It can also be inherited through nuclear inheritance patterns, including X-linked, autosomal recessive, and autosomal dominant manners.

Since 1988, the circle of mtDNA has become crowded with pathogenic mutations, and the principles of mitochondrial genetics should, therefore, be familiar to the practicing physician.

Heteroplasmy and threshold effect. Each cell contains hundreds or thousands of mtDNA copies, which, at cell division, distribute randomly among daughter cells. In normal tissues, all mtDNA molecules are identical (homoplasmy). Deleterious mtDNA mutations usually (but not always) affect only some (but not all) mtDNAs. The clinical expression of a pathogenic mtDNA mutation is largely determined by the relative proportion of normal and mutant genomes in different tissues. A minimum critical number of mutant mtDNAs is required to cause mitochondrial dysfunction in a particular organ or tissue and mitochondrial disease in an individual (threshold effect). Studies examining a known mtDNA mutation, m.3243 A>G, demonstrated that the amount of heteroplasmy in blood and urine > muscle and blood > muscle and urine seemed to correlate with disease severity (31).

Mitotic segregation. At cell division, the proportion of mutant mtDNAs in daughter cells may shift, and the phenotype may change accordingly. This phenomenon, called “mitotic segregation,” explains how the clinical phenotype may change in certain patients with mtDNA-related disorders as they grow older.

Maternal inheritance. At fertilization, all mtDNA derives from the oocyte. Therefore, the mode of transmission of mtDNA and mtDNA point mutations (single deletions of mtDNA are usually sporadic events) differs from Mendelian inheritance. A mother carrying an mtDNA point mutation will pass it on to all her children (boys and girls), but only her daughters will transmit it to their progeny.

Nuclear DNA (nDNA). In the last several years, there has been an increasing recognition that mitochondrial disease is not just inherited as mtDNA but also is from both parents through genes passed on by the nucleus.

For the most part, most nuclear-inherited mitochondrial disorders are inherited in an autosomal recessive manner such that both parents are carriers and the affected offspring has two defective copies of the gene causing the mitochondrial disease. However, X-linked and autosomal dominant inheritance also occur. A common example of X-linked is pyruvate dehydrogenase deficiency from mutations in the PDHA1 subunit located on the X chromosome. Disorders from the autosomally located POLG can be inherited in an autosomal dominant and an autosomal recessive manner, depending on the type of variation.

Abnormal oxidative phosphorylation from abnormal respiratory chain enzymes is not the only cause of mitochondrial disease. Mitochondrial oxidative phosphorylation is dependent on numerous processes. The respiratory chain subunits must be encoded. The actual electron channel is usually encoded by mtDNA and the support system by nuclear DNA. These subunits must be assembled (usually inherited through nuclear DNA). Protein synthesis within the mitochondria is dependent on translation by mitochondrial-specific ribosomal RNA (encoded by mtDNA) as well as transfer RNA (encoded by mtDNA), which are loaded by tRNA synthases (which are encoded by nuclear DNA). Nuclear genes encode mtDNA maintenance and replication. The mitochondria themselves move, join, and separate (fusion, fission, and motility) and are encoded by nuclear genes. Mitochondria are also dependent on having appropriate lipid bilayers that are built from proteins encoded by nuclear genes. As you can see, normal mitochondrial function is a complex orchestration between mtDNA and nuclear DNA and is still not entirely understood.

To best understand testing, a classification using the two major categories, disorders due to defects of mtDNA and disorders due to defects of nDNA can be used.

Disorders due to defects of mtDNA

Clinically named disorders. Many of the initial mitochondrial disorders were diagnosed based on clinical findings. Several of these were then found to have mtDNA causes. Of important note, as nuclear genes have also been identified, this association is not always true, so the clinical phenotype is important to naming, but the initial description of cause (mtDNA point mutation or deletion) is not always found, and a nuclear mutation is found instead.

Causes of these named disorders include mitochondrial DNA rearrangements (single deletions or duplications) and point mutations.

Disorders initially attributed to mtDNA rearrangements and single deletions of mtDNA. These include three sporadic conditions: Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia with or without proximal limb weakness.

Pearson syndrome is usually a fatal disorder in infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction.

Kearns-Sayre syndrome is a multisystem disorder of impaired eye movements (progressive external ophthalmoplegia), pigmentary retinopathy, and heart block, with onset before the age of 20. Frequent additional signs include ataxia, dementia, and endocrinopathies (diabetes mellitus, short stature, hypoparathyroidism). Lactic acidosis, elevated CSF protein (over 100mg/dl), and scattered COX-negative ragged-red fibers in the muscle biopsy are typical laboratory abnormalities. This is one of the earlier described disorders.

Progressive external ophthalmoplegia with or without proximal limb weakness. It is often compatible with a normal lifespan. Deletions within the mtDNA vary in size and location, but a “common” deletion of 5 kb is frequently seen in patients and in aged individuals (66; 65).

Point mutations within the mtDNA. These are common, with over 250 pathogenic point mutations having been identified in mtDNA from patients with various disorders. Most are maternally inherited and multisystemic (52), but some are sporadic and tissue specific. Among the maternally inherited encephalomyopathies, four syndromes are more common.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) typically, but not always, presents in children or young adults after normal early development. Symptoms include recurrent vomiting, migraine-like headache, and stroke-like episodes causing cortical blindness, hemiparesis, or hemianopia. These symptoms often are progressive, leading to greater morbidity and, potentially, mortality. MRI of the brain shows “infarcts” that do not correspond to the distribution of major vessels, raising the question of whether the strokes are vascular or metabolic in nature (48). The most common mtDNA mutation is m.3243A>G in the tRNA(Leu)(UUR) gene, but about a dozen other mutations have been associated with MELAS, most notably a mutation (m.13513G> A) in the ND5 gene, which encodes subunit 5 of complex I (68). Notably, most maternal relatives of a typical MELAS patient carry the mutation in low abundance and are either mildly affected or unaffected due to heteroplasmy. In agreement with this observation, two epidemiological studies have reported comparably high prevalence (about 1 in 750) of the m.3243A>G mutation in the normal population (49; 23), and one of them has found that the prevalence of pathogenic mtDNA mutations is 1 in 200 individuals in northern England.

MERRF (myoclonus epilepsy with ragged-red fibers), characterized by myoclonus, weakness, ataxia, seizures, hearing loss, dementia, multiple lipomas, and neuropathy (47). Three mtDNA mutations (m.8344A> G, m.8356T> C, m.8363G> A) have been associated with MERRF, and all are in the tRNA(Lys) gene.

The third syndrome comes in two phenotypes: (1) neuropathy, ataxia, and retinitis pigmentosa (NARP) usually affecting young adults and causing retinitis pigmentosa, dementia, seizures, ataxia, proximal weakness, and sensory neuropathy (35) or (2) maternally inherited Leigh syndrome (MILS), a severe infantile encephalopathy with characteristic symmetrical lesions in the basal ganglia and the brainstem (63).

Leber hereditary optic neuropathy (LHON), is characterized by acute or subacute loss of vision in young adults, more frequently males, due to bilateral optic atrophy (11). Three mtDNA point mutations in ND genes are often homoplasmic and account for more than 90% of Leber hereditary optic neuropathy cases. These are m.11778G>A in ND4, m.3460G>A in ND1, and m.14484T>C in ND6.

Because mitochondria are present in all tissues, syndromes associated with mtDNA mutations can affect every system in the body, including the eye (optic atrophy, retinitis pigmentosa, cataracts), hearing (sensorineural deafness), endocrine system (short stature, diabetes mellitus, hypoparathyroidism), heart (familial cardiomyopathies, conduction blocks), gastrointestinal tract (exocrine pancreas dysfunction, intestinal pseudo-obstruction, gastroesophageal reflux), and kidney (renal tubular acidosis, nephrotic syndrome). Any combination of the symptoms and signs listed above should raise the suspicion of a mitochondrial disorder, especially if there is evidence of maternal transmission.

On the other hand, point mutations in mtDNA protein-coding genes often escape the rules of mitochondrial genetics in that they affect single individuals and single tissues, most commonly skeletal muscle (04). Thus, patients with exercise intolerance, myalgia, and sometimes recurrent myoglobinuria may have isolated defects of complex I, complex III, or complex IV due to pathogenic mutations in genes encoding ND subunits, cytochrome b, or COX subunits. The lack of maternal inheritance and the involvement of muscle alone suggest that mutations arose de novo in myogenic stem cells after germ-layer differentiation (“somatic mutations”) (17).

Respiratory chain oxidative phosphorylation enzymes. Oxidative phosphorylation by the respiratory chain utilizes reducing substances to produce an electron gradient that drives the ATP synthase. Abnormalities of specific complexes of the respiratory chain (eg, complex 1/COX1) can be seen in biopsy specimens of affected tissues. Historically, muscle biopsies were used for diagnosis. Biochemical testing of a tissue that shows abnormalities of oxidative phosphorylation may not be abnormal in the genes that encode the complexes because abnormal enzyme activity can also be seen in secondary mitochondrial disease (eg, abnormal TCA cycle, pathways of abnormal amino acid catabolism), physiological or psychiatric stress, or abnormal biopsy collection (57). Biopsy enzyme assays and staining are more likely to be useful in confirming genetic diagnosis or if a genetic diagnosis cannot be identified (57).

Disorders due to defects of nDNA

Disorders caused by pathogenic variants in nuclear DNA (nDNA) account for approximately 90% of mitochondrial disease genes, with more than 350 to 400 nuclear genes now recognized as potential causes (30; 02; 60; 54). These conditions differ substantially from mtDNA-related disorders in inheritance patterns, clinical presentation, and pathogenic mechanisms.

Inheritance patterns

nDNA-related mitochondrial diseases follow Mendelian inheritance, predominantly autosomal recessive, though autosomal dominant and X-linked forms also occur (30; 02; 60; 54). This contrasts sharply with mtDNA disorders, which are maternally inherited or sporadic (75).

Because most nDNA disorders are autosomal recessive, affected siblings typically exhibit remarkably similar phenotypes, often becoming symptomatic in infancy or early childhood with uniformly severe, progressive courses. In one comparative study, seven of eight children with nuclear gene mutations died during the first decade of life, whereas siblings with mtDNA mutations displayed a broader clinical spectrum, with onset ranging from childhood to adulthood (except for Leigh syndrome) and comparatively milder progression (75).

Clinical presentation and disease course

nDNA mutations most commonly present in infancy or childhood and are frequently fatal, although adult-onset forms are recognized (75; 60). Although many phenotypes overlap with mtDNA-related disease—such as cardiomyopathy, encephalopathy, and Leigh syndrome—some presentations are particularly associated with nuclear defects.

GRACILE syndrome is caused by BCS1L mutations and causes growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death (75).

LBSL (leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate) is caused by DARS2 mutations (75).

Mohr–Tranebjaerg syndrome (deafness–dystonia) is caused byTIMM8A mutations (75).

nDNA mutations typically exhibit minimal intrafamilial variability with uniformly severe phenotypes, whereas mtDNA mutations show marked variation in onset and severity due to heteroplasmy and tissue-specific distribution (75).

Categories of nuclear gene defects

Structural subunits of respiratory chain complexes. Pathogenic variants have been identified in nuclear-encoded subunits of complexes I, II (entirely nuclear-encoded), III, and IV. These mutations produce isolated biochemical deficiencies of the affected complex, with normal mtDNA copy number and no mtDNA deletions (30). Complex II defects are rare but have been associated with Leigh syndrome and tumors, such as carotid body paragangliomas and pheochromocytomas (75).

Assembly factors and chaperone proteins. Numerous nDNA genes encode assembly factors required for proper formation of the respiratory chain complexes (30). Examples include SCO1 mutations causing complex IV deficiency with encephalomyopathy and hepatopathy and BCS1L mutations resulting in complex III deficiency and GRACILE syndrome (75).

mtDNA maintenance genes. Mutations in nuclear genes involved in mtDNA replication, transcription, and maintenance lead to secondary mtDNA abnormalities—multiple deletions or mtDNA depletion—a key pathogenic distinction from primary mtDNA mutations (30).

Key gene categories include mtDNA replication machinery (POLG, POLG2, TWNK, TFAM, RNASEH1, MGME1, DNA2); nucleotide pool maintenance (TK2, DGUOK, SUCLG1, SUCLA2, ABAT, RRM2B, TYMP, SLC25A4, AGK, MPV17); and mitochondrial dynamics (OPA1, MFN2, FBXL4) (75).

Autosomal dominant mutations in POLG and TWNK cause multiple mtDNA deletions with variable impairment of complexes I, III, IV, and V. Complex II remains preserved because its components are exclusively nuclear-encoded (30). Autosomal recessive variants may cause either mtDNA depletion or multiple deletions. Clinical presentations range from severe infantile myopathy or hepatocerebral disease to adult-onset ophthalmoplegia, myopathy, encephalopathy, polyneuropathy, reduced fertility, and parkinsonism (75).

Coenzyme Q10 (CoQ10) biosynthesis and secondary CoQ10 deficiency. CoQ10 deficiency represents a heterogeneous but often treatable mitochondrial disorder.

Primary CoQ10 biosynthesis gene defects occur in PDSS1, PDSS2, COQ2, COQ4, COQ6, COQ9, and ADCK3/CABC1.

Clinical phenotypes include the following (75; 07):

(1) Myopathy with recurrent myoglobinuria
(2) Cerebellar atrophy with encephalopathy
(3) Isolated myopathy with ragged-red fibers
(4) Infantile multisystem encephalomyopathy
(5) Nephrotic syndrome ± neurologic disease
(6) Variable multisystem involvement from COQ4 mutations

Secondary CoQ10 deficiency occurs in APTX (AOA1), ETFDH, and ANO10 mutations.

Therapeutic relevance. Many patients show clinical improvement with high-dose CoQ10 supplementation.

Toxic indirect assembly defects. Some metabolic disorders cause toxic inhibition of respiratory chain function. Ethylmalonic encephalomyopathy, caused by ETHE1 mutations, leads to accumulation of sulfide, a potent inhibitor of COX. Clinical features include chronic diarrhea, vasculopathy, encephalopathy, and elevated ethylmalonic acid.

Mitochondrial protein import disorders. Mitochondrial import machinery is essential for trafficking of nuclear-encoded mitochondrial proteins. Mohr–Tranebjaerg syndrome, caused by TIMM8A mutations, results in progressive deafness, dystonia, cortical blindness, and psychiatric abnormalities. These disorders demonstrate that mitochondrial dysfunction can arise even when respiratory chain components are intact.

Inner mitochondrial membrane lipid defects. Respiratory chain function requires proper membrane lipid composition, particularly cardiolipin. Examples include the following:

AGK	Sengers syndrome	Cardiomyopathy, cataracts, lactic acidosis
CHKB deficiency		“Megaconial myopathy” with giant mitochondria
LPIN1		Childhood recurrent rhabdomyolysis
SERAC1	MEGDEL syndrome	Dystonia–encephalopathy with deafness
TAZ	Barth syndrome	Cardiomyopathy, neutropenia, skeletal myopathy

Defects in mtDNA translation and intergenomic communication. These disorders affect translation of the 13 mtDNA-encoded respiratory chain proteins.

Key genes include the following: EFG1, EFTu, TSFM, MRPS16, PUS1, and numerous mitochondrial aminoacyl-tRNA synthetases (DARS2, AARS, RARS2, etc) (Schapira 2012; 30; 75).

Associated phenotypes include the following:

• Infantile encephalomyopathy
• Cardiomyopathy
• Sideroblastic anemia
• LBSL (DARS2)
• Charcot–Marie–Tooth neuropathy (AARS)
• Pontocerebellar hypoplasia (RARS2)
• Lactic acidosis and encephalopathy

Pathogenic mechanisms

Pathogenic mechanisms differ fundamentally between nDNA and mtDNA disorders.

nDNA defects typically cause direct impairment of respiratory chain complex assembly or function; secondary mtDNA abnormalities (depletion or multiple deletions) affecting multiple complexes; disrupted mitochondrial dynamics, biogenesis, or quality control; and imbalances in mitochondrial nucleotide pools (Schapira 2012; 30; 75).

mtDNA defects operate through heteroplasmy and threshold effects (typically 60% to 90% mutation load for biochemical expression); mitotic segregation and clonal expansion; tissue-specific distribution of mutant mtDNA; and maternal inheritance shaped by the genetic bottleneck (75).

Diagnostic implications

Biochemical patterns help differentiate nuclear from mtDNA disorders. nDNA mutations affecting respiratory chain subunits or coenzyme Q10 biosynthesis typically produce isolated complex deficiencies with normal mtDNA copy number (30). In contrast, mutations in nDNA genes responsible for mtDNA maintenance result in combined deficiencies of complexes I, III, IV, and V with measurable mtDNA depletion or multiple deletions; complex II remains preserved (30). mtDNA mutations variably affect complexes I, III, IV, or V depending on the specific mutation, but complex II is always unaffected (75).

Pathogenesis

The literature emphasizes that mitochondrial disease pathogenesis extends far beyond isolated defects in cellular energy production, with multiple interconnected mechanisms contributing to dysfunction (21; 54). The historical assumption that ATP deficiency alone explains disease manifestations has been challenged by inconsistent detection of measurable energy deficits in vitro and in vivo (21).

The current understanding recognizes several primary pathogenic mechanisms. Defective oxidative phosphorylation (OXPHOS) affects ATP synthesis (21; 60). Other mechanisms include increased reactive oxygen species production or decreased antioxidant protection; loss of mitochondrial membrane potential; impaired mitochondrial calcium handling; activation of apoptotic pathways; and aberrant calcium homeostasis and dysregulated apoptosis (64; 21).

Genetic complexity continues to expand, with defects identified in more than 350 genes across the nuclear and mitochondrial genomes. These mutations disrupt diverse mitochondrial functions, including OXPHOS structural subunits and assembly factors, mtDNA maintenance and replication, mitochondrial translation, lipid metabolism, and mitochondrial dynamics (fusion and fission) (02; 75).

Multi-omic studies have revealed novel mechanistic insights. For example, mutations in SLC25A46 implicate defects in the mitochondrial contact site and cristae organizing system (MICOS), altered mitochondrial dynamics, and impaired lipid homeostasis through interactions with the endoplasmic reticulum membrane protein complex. These findings underscore that abnormal mitochondrial ultrastructure, disrupted mtDNA segregation, and dysfunctional OXPHOS often arise from complex interplay among mitochondrial proteins rather than isolated pathway defects (02).

Tissue specificity is a hallmark of mitochondrial disease, with high–energy demand organs—particularly muscle and brain—most frequently affected, although the biological basis of this selectivity remains incompletely understood (43; 55).

Classic mitochondrial syndromes

There are several well-defined clinical syndromes (64).

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is characterized by stroke-like episodes in nonvascular distributions.

MERRF (myoclonic epilepsy and ragged red fibers) features myoclonus and seizures.

Leber hereditary optic neuropathy is characterized by isolated optic nerve involvement.

Kearns-Sayre syndrome is characterized by chronic progressive external ophthalmoplegia (CPEO), retinopathy, and cardiac conduction defects.

NARP is characterized by neuropathy, ataxia, and retinitis pigmentosa.

Leigh syndrome (maternally inherited Leigh syndrome, MILS) is a subacute necrotizing encephalomyelopathy.

Organ-specific manifestations

Tissues with high energy requirements are preferentially affected, though the mechanisms underlying tissue selectivity remain incompletely understood.

Neurologic. Epileptic seizures, stroke-like episodes, ataxia, peripheral neuropathy, dementia, migraine, movement disorders (parkinsonism, dystonia, chorea), and spasticity (15; 43).

Ophthalmologic. External ophthalmoplegia, ptosis, optic atrophy, and pigmentary retinopathy (15).

Cardiac. Cardiomyopathy, heart block, and Wolff-Parkinson-White arrhythmia (64).

Endocrine. Diabetes mellitus and deafness (maternally inherited diabetes and deafness syndrome), growth problems, and hypoparathyroidism (15; 55).

Muscular. Proximal myopathy, exercise intolerance, and myoglobinuria (64; 15).

Other systems. Sensorineural hearing loss, hepatopathies, nephropathies, gastrointestinal problems (21; 08).

Clinical recognition

Deep phenotyping is critical for recognizing mitochondrial disease (54). Although some patients fit classic syndromes, most present with nonclassical multisystem involvement. Common clinical features include ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus (15). The presence of more than two such manifestations should raise suspicion for a mitochondrial disorder (43).

Genotype-phenotype correlations

The m.3243A>G variant, one of the most prevalent mtDNA mutations, exemplifies phenotypic diversity in mitochondrial disease. It commonly presents with diabetes and deafness, myopathy, cardiac disease, stroke-like episodes, and gastrointestinal disturbances. Disease heterogeneity results from factors, including mtDNA heteroplasmy, mtDNA copy number, and nuclear genetic modifiers (08).

Mitochondrial diseases can present at any age, with both mtDNA and nuclear DNA disorders now recognized across the lifespan. A high incidence of mid- and late-pregnancy loss is also a common feature (15).

Therapy

Treatment for mitochondrial disorders remains largely symptomatic and supportive, as no curative therapies currently exist for most conditions. Optimal management requires a coordinated, multidisciplinary approach tailored to the specific manifestations affecting each organ system. Although supportive care continues to form the cornerstone of treatment, a limited number of targeted therapies are beginning to emerge. Notably, elamipretide is the first FDA-approved agent for a primary mitochondrial disorder; it is indicated for Barth syndrome in patients weighing at least 30 kg (37).

General supportive measures. Vitamins and cofactors are commonly used despite limited evidence from controlled trials (37). Antioxidants include coenzyme Q10 for primary coenzyme Q10 deficiency (requires high doses), idebenone, vitamin C, vitamin E, alpha-lipoic acid, and N-acetylcysteine. Respiratory chain cofactors include thiamine for thiamine-responsive Leigh syndrome and riboflavin, which is effective in some complex I deficiencies (38). Compounds correcting secondary deficiencies include carnitine for primary carnitine deficiency and creatine. Dichloroacetate showed improvement in venous lactate and magnetic resonance spectroscopy in children but caused peripheral nerve toxicity in long-term adult trials.

Exercise training has shown benefits in some patients (38; 62). Aerobic exercise and resistance training improved muscle strength in adults with single, large-scale mtDNA deletions. Endurance training improved oxidative phosphorylation capacity and exercise tolerance. "Gene shifting" through resistance training may lower heteroplasmy by stimulating satellite cell fusion.

Management should also include avoidance of mitochondrion-toxic agents, including valproate, aminoglycosides, and certain anesthetics. Nutritional management with individually tailored diets and physical training programs should be offered to all patients, as well as treatment of the underlying organ system abnormalities.

Neurologic manifestations. Stroke-like episodes in MELAS syndrome can be treated with L-arginine, which acts as a vasodilator and nitric oxide precursor. L-arginine appears promising for both acute treatment and prophylaxis of stroke-like episodes (56; 54). Citrulline, another nitric oxide precursor, represents an alternative approach (22).

Epilepsy and seizures require standard antiepileptic medications tailored to seizure type and patient tolerance (27).

Peripheral neuropathy management focuses on symptomatic relief, though caution is warranted with certain treatments. Long-term dichloroacetate (DCA) trials in adults were terminated due to peripheral nerve toxicity (58; 56).

Ophthalmologic manifestations. Leber hereditary optic neuropathy can be treated with idebenone, the only disease-modifying treatment approved to date for this condition. Early and prolonged idebenone treatment improved visual recovery frequency and possibly altered natural history (39; 53). Intravitreal gene therapy is pending approval from the European Medicines Agency (54). EPI-743 showed arrested disease progression and vision improvement in small trials, with some patients achieving total recovery of visual acuity (74).

Dominant optic atrophy showed some improvement with idebenone in a small pilot trial (53).

Cardiac manifestations. Barth syndrome can now be treated with elamipretide, which received FDA approval in September 2025 for patients weighing at least 30 kg. Elamipretide is a cardiolipin protector that targets mitochondrial dysfunction (37; 73).

Cardiomyopathy management includes standard heart failure therapies, with coenzyme Q10 supplementation potentially beneficial in primary or secondary coenzyme Q10 deficiency (39; 53).

Gastrointestinal and hepatic manifestations. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) due to thymidine phosphorylase deficiency can be treated (56; 54). Allogeneic hematopoietic stem-cell transplantation can potentially halt disease progression (though morbidity and mortality are high if general condition is compromised, requiring timely diagnosis). Orthotopic liver transplantation has been used to treat. Platelet infusions transiently restore circulating thymidine phosphorylase. Enzyme replacement therapy encapsulated in red cell ghosts is used in patients whose condition precludes stem cell transplantation.

Metabolic and endocrine manifestations. Diabetes mellitus requires standard glycemic control with insulin or oral hypoglycemic agents, avoiding metformin in patients with significant lactic acidosis risk (27).

Lactic acidosis has been treated with dichloroacetate, which showed statistically significant improvement in venous lactate in pediatric trials; however, clinical benefit was limited, and adult trials showed peripheral nerve toxicity (58; 41; 56).

Muscular manifestations. Exercise intolerance and myopathy can be of benefit. Aerobic exercise and resistance training improved muscle strength and post-exercise lactate in some studies, though benefits are lost with cessation (56; 15). A gene shifting approach using resistance training to stimulate muscle regeneration potentially lowers heteroplasmy levels through satellite cell fusion (15). Creatine monohydrate showed mixed results, with one trial reporting improved muscle strength but two subsequent trials showing no benefit (58; 41).

NAD+ deficiency in mitochondrial myopathy showed improvement with niacin (vitamin B3) supplementation, which restored NAD+ levels and improved muscle strength, performance, and metabolome in a pilot study (54).

Renal manifestations. Renal tubular dysfunction requires electrolyte replacement and management of Fanconi syndrome when present (27).

Emerging experimental therapies

Novel pharmacological agents are under investigation (36; 74). EPI-743, a parabenzoquinone analogue targeting oxidative stress, showed improvement in Leigh syndrome and LHON in early trials. KH176, a modified redox modulating agent, is in phase 2 trials. Niacin (vitamin B3) showed improved muscle strength and metabolome in a pilot study of mitochondrial myopathy.

Elamipretide. Elamipretide, a cardiolipin protector, shows promise beyond its approved Barth syndrome indication. In September 2025, elamipretide received FDA approval for Barth syndrome in patients weighing at least 30 kg, representing the first approved cardiolipin protector for mitochondrial disease (FDA Orange Book 2025). The drug has been well-tolerated across trials, with injection site reactions being the most common adverse event (80% in MMPOWER-2), mostly mild (39). No serious adverse events or deaths were reported in the phase 3 trial (37).

Mechanism of action. Elamipretide is a mitochondria-targeting tetrapeptide that selectively binds cardiolipin in the inner mitochondrial membrane, stabilizing mitochondrial cristae structure, reducing oxidative stress, and enhancing ATP production. It modulates mitochondrial membrane electrostatic potentials and facilitates assembly of cardiolipin-dependent proteins centrally involved in mitochondrial physiology (62).

Clinical trial data. The 2023 MMPOWER-3 phase 3 trial enrolled 218 adults with genetically confirmed primary mitochondrial myopathy and failed to meet its primary endpoints. The difference in 6-minute walk test (6MWT) distance between elamipretide (40 mg/day subcutaneously) and placebo at 24 weeks was -3.2 meters (95% CI: -18.7 to 12.3; p=0.69), and the Primary Mitochondrial Myopathy Symptom Assessment total fatigue score showed no significant difference (-0.07; 95% CI: -0.10 to 0.26; p=0.37) (37).

However, genotype-specific post hoc analyses revealed important subgroup effects. Patients with nuclear DNA (nDNA) pathogenic variants, particularly those with mtDNA replisome disorders (POLG and TWNK mutations), showed improvement on the 6MWT trending toward significance (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo; p=0.06). Patients with chronic progressive external ophthalmoplegia and replisome variants demonstrated significant benefit (37.3 ± 9.5 m versus -8.0 ± 10.7 m for placebo; p=0.0024). In contrast, patients with mtDNA pathogenic variants or single large-scale mtDNA deletions (74% of the population) showed no benefit (38).

Idebenone. Idebenone is the only disease-modifying treatment approved by the European Medicines Agency for Leber hereditary optic neuropathy. The recommended dose is 300 mg three times daily with meals. The response rate is 34% after 1 year and 52% after 2 years, though response is only partial in most cases, and about half of patients appear unresponsive (74).

Mechanism of action. Idebenone is a synthetic short-chain analogue of ubiquinone that bypasses complexes I and II, shuttling electrons directly to complex III. Its activity is critically dependent on NAD(P)H:quinone oxidoreductase 1 (NQO1), the major enzyme involved in idebenone activation (36; 74).

The RHODOS randomized placebo-controlled trial failed to demonstrate superiority over placebo in primary endpoints, but cumulative evidence from retrospective data and real-world expanded access programs supported regulatory approval. Treatment should be initiated as soon as possible, ideally within the first year of disease onset, and continued for at least 1 year to assess benefit (74).

Safety and limitations. Idebenone has a narrow therapeutic window and NQO1-dependent toxicity profile. In NQO1-deficient cells, idebenone causes a marked decrease in viability, ROS production, and deleterious effects on ATP levels. This NQO1 dependence may explain the high variability in therapeutic outcomes between patients. Idebenone-induced toxicity has been demonstrated in mouse retina ex vivo, correlating with variation in NQO1 expression between retinal cell types (74).

In cortical neurons (which have poor NQO1 expression), idebenone reduced respiratory capacity rather than supporting it, whereas astrocytes (with higher NQO1) showed stimulated respiration and complex I bypass activity. This fundamental difference may explain limited efficacy in some neurodegenerative disease trials (36).

Gene therapy approaches

Leber hereditary optic neuropathy. Lenadogene nolparvovec has shown the greatest clinical progress, with phase 3 trials demonstrating efficacy and good tolerability (42). Intravitreal gene therapy for Leber hereditary optic neuropathy is pending approval from the European Medicines Agency (74; 53).

AAV-based gene replacement. Recombinant adeno-associated virus (rAAV) gene replacement has been successfully undertaken in more than 10 preclinical mouse models of primary mitochondrial diseases, including Leigh syndrome, Barth syndrome, and ethylmalonic encephalopathy. Novel rAAV technologies have achieved more efficient organ targeting (33; 42).

Mitochondrial DNA editing. Several approaches are under development for mtDNA disorders (42). Nuclease-based strategies (TALENs, zinc-finger nucleases, meganucleases like mitoARCUS) that degrade mtDNA molecules with pathogenic variants have been successfully delivered in vivo in mice using rAAV vectors. CRISPR-Cas9 gene editing has achieved in vivo editing in mouse models of nuclear gene-related primary mitochondrial diseases. CRISPR-free gene editing approaches show great potential for mtDNA disorders. AI-driven metabolic profiling personalizes mitochondrial-targeted interventions.

Challenges. Some major obstacles to clinical translation include achieving adequate organ transduction, particularly for CNS and muscle; targeting mitochondrial genomes due to mitochondrial membrane impermeability; clinical trial design for rare, heterogeneous conditions; safety concerns with genome editing technologies; and regulatory requirements for novel therapeutic modalities (26; 42).

Allotopic expression. One promising approach delivers wild-type mtDNA genes using viral vectors that remain in the cytosol, with mitochondrial targeting signals facilitating protein transport into mitochondria (54). This bypasses the challenge of mitochondrial membrane impermeability.

Gene therapy approaches are in development, including allotopic expression (delivering wild-type mtDNA genes via viral vectors) and mitochondrial base editing, though mitochondrial membrane impermeability poses challenges (26; 42).

Acting on pathogenesis

Removing noxious compounds. The most logical intervention in any inborn error of metabolism appears to be removing noxious compounds. In most mitochondrial encephalomyopathies, the obvious culprit is lactic acid. Bicarbonate therapy is common and almost “automatic” but should be used prudently (61). Dichloroacetate inhibits pyruvate dehydrogenase kinase, keeping pyruvate dehydrogenase in the dephosphorylated, active form, thus, favoring pyruvate metabolism and lactate oxidation. Although oral dichloroacetate was well tolerated in randomized studies of children with congenital lactic acidosis and heterogeneous mitochondrial diseases, it did not improve neurologic outcomes in patients with MELAS and was associated with evidence of peripheral neuropathy (40). In MNGIE, the toxic metabolites that accumulate in blood as a direct consequence of the thymidine phosphorylase defect are thymidine and deoxyuridine (71). Hemodialysis was only transiently effective in lowering blood levels, whereas the effect of allogeneic stem cell transplantation was more substantial and permanent, as discussed above.

Administration of electron acceptors. This is most effective in disorders due to primary defects of such acceptors, best exemplified by primary CoQ10 deficiencies. However, at least one child with Leigh syndrome and CoQ10 deficiency due to mutations in the PDSS2 gene did not respond to CoQ10 administration, possibly because therapy was started too late, because the dose was inadequate, or because the energy defect was too drastic (46). In patients with secondary CoQ10 deficiency, the response to supplementation is generally good but unpredictable and often variable. For example, patients with the myopathic form of glutaric aciduria type II due to electron transfer flavoprotein dehydrogenase deficiency may need both CoQ10 and riboflavin for optimal response (29). In patients with complex I deficiency due to mutations in ACAD9, a flavoprotein-containing protein, administration of riboflavin has been beneficial (28). Ubiquinol is the preferred form of CoQ10 due to its improved bioavailability, but much of the dosing has been determined with ubiquinone (06).

“Cocktails” of vitamins and cofactors. These are the most widely used therapy in clinical practice. Although there is little evidence of their benefit (10), vitamin and cofactor supplementation has been used based on the underlying pathophysiology, and with an intelligent approach, it may show some benefit (06).

In the hope of facilitating ATP production by a sluggish respiratory chain, electron flux is “boosted” by the addition of electron acceptors (CoQ10, vitamin C, vitamin K, succinate). Alternatively, we try to boost the synthesis of a naturally occurring high-phosphate compound, phosphocreatine by administering creatine. L-carnitine is prescribed because plasma-free carnitine tends to be lower and esterified carnitine higher than normal, probably reflecting a partial impairment of beta-oxidation. Folic acid deserves special mention because early observations had shown that it was decreased in the CSF of patients with Kearns-Sayre syndrome, and a study documented both clinical and neuroradiological improvement in a child after 1 year of monotherapy with 2.2 mg folinic acid/kg daily, suggesting that early and aggressive administration of this compound should be tried in this devastating condition (59).

Riboflavin and magnesium are both growing in terms of acceptance as therapies for migraines associated with mitochondrial disease (06).

A compound, a parabenzoquinone labeled EPI-743 is being tested in infants and children with Leigh syndrome (25; 50), but has not shown to be as promising as initially thought.

To improve ATP synthesis, creatine monohydrate supplementation has been used, but the only two randomized studies came to different conclusions, possibly due to the difference in muscle phosphocreatine concentration between the two groups (72; 44).

Scavenging excessive reactive oxygen species. This is probably the most common approach not just to mitochondrial diseases due to respiratory chain defects but also to late-onset neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease, in which there is direct or indirect evidence of oxidative stress. Antioxidants used in clinical practice include vitamin E, CoQ10, idebenone, glutathione, and dihydrolipoate.

As mentioned above, CoQ10 is useful in primary CoQ10 deficiencies, but it is also widely prescribed to patients with respiratory chain disorders. Although anecdotal reports (too numerous to be cited here) are generally positive, we still lack a rigorous double-blind trial. However, clinical experience teaches that CoQ10 needs to be administered at high doses (no less than 300 mg daily in adults), which fortunately have shown to be well tolerated in numerous studies of large cohorts.

Importantly, initial studies of idebenone had suggested a beneficial effect only on the cardiopathic component of Friedreich ataxia, but a standardized study showed a dose-related beneficial effect also on the neurologic component of the disease (51; 67). Idebenone is now a recommended treatment of Leber hereditary optic neuropathy (13; 12).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Georgette Dib MD

Dr. Dib of Cleveland Clinic has no relevant financial relationships to disclose.
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Miriam Bekhit MD

Dr. Bekhit of Cleveland Clinic Foundation has no relevant financial relationships to disclose.
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Editor

Nicholas E Johnson MD MSCI FAAN

Dr. Johnson of Virginia Commonwealth University received consulting fees and/or research grants from AMO Pharma, Avidity, Dyne, Novartis, Pepgen, Sanofi Genzyme, Sarepta Therapeutics, Takeda, and Vertex, consulting fees and stock options from Juvena, and honorariums from Biogen Idec and Fulcrum Therapeutics as a drug safety monitoring board member.
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Former Authors

Salvatore DiMauro MD
Kimberly A Chapman MD PhD
Emma Ciafaloni MD FAAN

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor

heredity typical
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD-10: Mitochondrial myopathy, not elsewhere classified: G71.3

Leigh syndrome: G31.82

Alpers syndrome: G31.81

Kearns-Sayre syndrome: H49.81

Leber hereditary optic neuropathy: H47.22

Other specified metabolic disorders: E88.8
ICD-11: Other specified mitochondrial myopathies: 8C73.Y

Mitochondrial myopathies, unspecified: 8C73.Z

Leigh syndrome: 5C53.24

Progressive external ophthalmoplegia: 9C82.0

Disorders of mitochondrial oxidative phosphorylation: 5C53.2

Other specified inborn errors of energy metabolism: 5C53.Y

Other specified metabolic disorders: 5D0Y

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Mitochondrial disorders

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Mitochondrial disorders

Cite this article

Introduction

Overview

Key points

Description

Disorders due to defects of mtDNA

Disorders due to defects of nDNA

Inheritance patterns

Clinical presentation and disease course

Categories of nuclear gene defects

Pathogenic mechanisms

Diagnostic implications

Pathogenesis

Classic mitochondrial syndromes

Organ-specific manifestations

Clinical recognition

Genotype-phenotype correlations

Therapy

Emerging experimental therapies

Gene therapy approaches

Acting on pathogenesis

Conclusion

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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