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Mitochondrial Disorders

  1. Sabine Hofmann,
  2. Matthias F Bauer

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005539



How to Cite

Hofmann, S. and Bauer, M. F. 2006. Mitochondrial Disorders. eLS. .

Author Information

  1. Academic Hospital, Munich-Schwabing, Germany

Publication History

  1. Published Online: 27 JAN 2006


  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

Mitochondria are essential components of eukaryotic cells. They play a pivotal role in many key aspects of cellular metabolism, but their primary function is the generation of adenosine triphosphate (ATP) via the pathways of oxidative phosphorylation. One of the earliest hints that mitochondrial dysfunction is also an important cause of human disease was in 1959, when Ernster described a patient with severe hypermetabolism whose skeletal muscle biopsy contained a large excess of mitochondria with abnormal morphology. The progress in the understanding of the molecular basis of mitochondrial disorders increased considerably after 1988, when the first pathogenic mutations in the mitochondrial DNA (mtDNA) were associated with human neurological disorders. It is now clear that mitochondrial disorders encompass a wide variety of clinical phenotypes primarily involving organs with high energy demands such as neuronal tissues, muscle, heart, the renal system and the endocrine system. Owing to the dual genetic control, defects of oxidative phosphorylation may be caused by mutations in mitochondrial and nuclear genes that lead to a complex array of inheritance patterns. See also Mitochondrial Disorders: Nuclear Gene Mutations, Mitochondrial Genome: Evolution, and Mutation Nomenclature

Mitochondrial Pathways

  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

Mitochondria are complex organelles made up by two highly specialized membrane systems, the outer and inner membrane, and two aqueous compartments, the matrix and the intermembrane space. They are the main site of ATP production during aerobic metabolism. As many as 34 of 36 molecules of ATP, synthesized during complete degradation of glucose to CO2 and H2O, are generated within mitochondria. Moreover, virtually all the ATP formed during the degradation of fatty acids via β-oxidation is produced in the mitochondria. The ATP is then released from the matrix space via specialized carrier proteins or is used for other purposes such as heat generation and the transport of molecules into or out of the organelle. Therefore, depending on their energy demand, eukaryotic cells harbor varying numbers of mitochondria, ranging from only a few in spermatozoa to several thousand in cells of the brain, muscle or heart. In the mitochondrion, various metabolic pathways are bundled. Fatty acids and carbohydrates fuel the mitochondrial energy production as main substrates under normal conditions (Figure 1). Degradation of distinct amino acids is an important source for the energy-generating metabolism of mitochondria in the postabsorptive state. In addition, mitochondria harbor parts of metabolic pathways such as iron metabolism and the urea cycle which do not contribute to ATP generation. Moreover, mitochondria were shown to influence cellular mechanisms and pathways located in the cytosol, that is, apoptotic cell death or insulin secretion. See also Apoptosis and the Cell Cycle in Human Disease, and Iron Metabolism: Disorders

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Figure 1. Mitochondrial structure and function. Mitochondria play an essential role in many aspects of cellular metabolism, but their primary function is the synthesis of adenosine triphosphate (ATP) via the pathways of oxidative phosphorylation. Mitochondria contain two different membranes, the outer and the inner membrane, which are separated by the intermembrane space. The surface area of the inner membrane is greatly increased by a large number of infoldings (cristae), which protrude into the matrix space. The outer membrane contains pore proteins that render it permeable for ions and small molecules. The inner membrane is impermeable and has a very high protein content. It contains the multisubunit complexes comprising the oxidative phosphorylation (OXPHOS) system, as well as various carrier proteins, such as the ATP/adenosine diphosphate (ADP) carrier, which mediate the transport of metabolites in and out of the matrix space. The matrix space is the site of the Krebs cycle, the pyruvate dehydrogenase complex and the enzymes of β-oxidation. Matrix proteins also comprise enzymes involved in synthesis or metabolism of amino acids, ketones, urea, pyrimidines, nucleotides and heme. OM: outer membrane; IM: inner membrane; IMS: intermembrane space.

Carbohydrates undergo glycolysis in the cytosol to produce pyruvate, which is then transported into the mitochondria and converted to acetyl coenzyme A (acetyl-CoA) by the pyruvate dehydrogenase (PDH) multienzyme complex in the mitochondrial matrix; fatty acids are transported into the mitochondria by carnitine palmitoyltransferase I and II (CPT I and II) in exchange for free carnitine and then degraded to acetyl-CoA via β-oxidation. In each revolution of the citric acid cycle (Krebs cycle), acetyl-CoA condenses with the four-carbon molecule oxaloacetate to form the six-carbon citrate, which is converted back to oxaloacetate by consecutive reactions that release two molecules of CO2 and generate three molecules of reduced nicotinamide adenine dinucleotide (NADH) and two of reduced flavin adenine dinucleotide (FADH2). Electrons from NADH and FADH2 are then transferred to O2 via a series of membrane-bound and mobile electron carriers, comprising the so-called respiratory chain (RC; Figure 2).

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Figure 2. Mitochondrial OXPHOS system. The respiratory chain consists of four high molecular weight complexes (I–IV). Complexes I, III and IV act as proton pumps, generating an electrochemical gradient across the inner membrane, which is then used by the F1F0–ATPase complex (complex V) to generate ATP from ADP and phosphate. Both the nuclear and the mitochondrial genome contribute to the biogenesis of these complexes in the mitochondrial inner membrane. Only complex II is made exclusively by nuclear-encoded polypeptide chains. The number of subunits contributed by the nuclear genome and mitochondrial genome are shown. Q: coenzyme Q; C: cytochrome c.

The RC is located within the inner mitochondrial membrane and consists of four multisubunit enzyme complexes, complexes I–IV, which are linked by the mobile electron carriers coenzyme Q10 (ubiquinone) and cytochrome c. Two of these complexes act as primary electron acceptors: complex I (NADH/ubiquinone oxidoreductase or NADH dehydrogenase) serves as an electron acceptor of several NADH-producing reactions, while complex II (succinate/ubiquinone oxidoreductase or succinate dehydrogenase) takes over electrons from succinate via FADH2 (Figure 2).

Within the complexes I, III and IV, the stepwise transport of electrons along the respiratory chain is coupled to a pumping mechanism that drives the translocation of protons from the matrix to the intermembrane space with a stoichiometry of 1H+/1e. The resulting proton-motive force is then used to drive ATP synthesis from adenosine diphosphate (ADP) by the ATP synthase complex (complex V). The entire process of the oxidation of fuel molecules by oxygen along the RC and the concomitant transfer of the resulting energy to the ATP synthesis is also summarized in the term ‘oxidative phosphorylation’ (OXPHOS).

Mitochondria are unique in such a way that two independently existing genomes contribute to the biogenesis of these organelles. While most of the mitochondrial proteins are encoded by nuclear genes and synthesized in the form of precursor proteins on cytosolic ribosomes, only 13 proteins – all of which are subunits of the OXPHOS system – are transcribed and translated from the mitochondrial genome (mtDNA). During the formation of new mitochondria by growth and division, nuclear-encoded proteins have therefore to be imported into mitochondria and sorted to their final destination. The translocation into and across both membranes is carried out in a multistep process which is facilitated by the action of independent translocation machineries in the mitochondrial outer and inner membranes. In order to form a functional OXPHOS system, mitochondrially encoded proteins have to be inserted into the mitochondrial inner membrane and assemble together with the nuclear-encoded subunits into hetero-oligomeric complexes in a coordinated manner. See also Molecular Machines and Human Disorders

Mitochondrial Genetics

  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

A human cell typically contains many mitochondria, each with multiple copies of the 16569-bp, circular, double-stranded mitochondrial genome. The mtDNA, fully sequenced in 1981, is a highly compact genome containing only a small noncoding region and 37 genes (Figure 3). These are the genes for ribonucleic acid (RNA) species (two ribosomal RNA, rRNAs; 22 transfer RNAs, tRNAs) required for mitochondrial protein biosynthesis and for the 13 polypeptides that represent subunits of the OXPHOS complexes I, III, IV and V (Figure 3). All of these latter proteins are synthesized on mitochondrial ribosomes and inserted from the matrix side into the mitochondrial inner membrane. See also Mitochondrial Genome

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Figure 3. Human mitochondrial genome. The mitochondrial DNA (mtDNA) is a 16569-bp-long, circular, double-stranded molecule. It contains 37 genes, which encode the RNA components of the mitochondrial translational apparatus, that is, the 22 transfer RNA (tRNA) and two ribosomal RNA (rRNA) species (12S rRNA, 16S rRNA), as well as 13 polypeptides, all of which are essential subunits of the OXPHOS complexes. The mtDNA is compact; it contains no introns and only one noncoding region of significant length, the ‘displacement loop’ (D-loop), which harbors the origin of replication of the heavy (H)-strand. The origin of replication of the light (L)-strand is located downstream at two-thirds of the mtDNA length. Replication of the mtDNA occurs independent of the cell-cycle phase and from replication of the nuclear DNA. Synthesis of each mtDNA strand thereby proceeds asynchronously from the two separate origins of replication. Both mtDNA strands are transcribed as polycistronic RNAs from their own promoters. To release functional RNA species (rRNA, tRNA, messenger RNA (mRNA)), these primary transcripts are processed by cleavage and modification. OH and OL: origins of H- and L-strand replication; HSP1 and HSP2: H-strand promoters; LSP: L-strand promoter; ND (-1, -2, -3, -4, -4L, -5, -6): genes for complex I reduced nicotinamide adenine dinucleotide (NADH) subunits; Cyt b: cytochrome b gene (complex III); COX (I, II, III): complex IV subunit genes; ATP (-6, -8): complex V subunit genes. Arrows: directions of DNA and RNA synthesis. See also Disease-related Genes: Functional Analysis

The unique features of mitochondrial genetics are essential for the understanding of the etiology and pathogenesis of mitochondrial disorders. Normally, all mitochondria of a human subject contain genetically identical mtDNA copies (homoplasmy). However, the mtDNA has a mutation rate approximately 10–20 times higher than that of the nuclear DNA. Owing to its compact structure, with the absence of introns and noncoding regions, a random mutation is likely to hit a functionally important gene. Once a mutation arises, cells initially contain a mixed population of wild-type and mutant mtDNA copies. This state is referred to as ‘heteroplasmy’. The mtDNA exhibits strict maternal inheritance, since it is exclusively transmitted from the mother's oocyte to her offspring, while no contribution comes from the male gamete. Once a heteroplasmic mutation is inherited from the mother or is occasionally acquired in one single mtDNA molecule during early embryogenesis, both normal and mutant mtDNA are randomly distributed during mitosis to the daughter cells (mitotic segregation). Therefore, it seems likely that the distribution of a heteroplasmic mutation among different organs depends on the time point at which the mutation occurs and on the developmental fate of the affected progenitor. See also Mitochondrial DNA: Fate of the Paternal Mitochondrial Genome, Mitochondrial DNA Polymorphisms, Mitochondrial Heteroplasmy and Disease, and Mitochondrial Non-Mendelian Inheritance: Evolutionary Origin and Consequences

Manifestation of a clinical phenotype depends on the pathogenic nature of a mutation, its tissue distribution and the relative reliance of the affected organ system on the mitochondrial energy supply. Moreover, the appearance of disease symptoms correlates with the amount of mutated mtDNA in an affected tissue and first occurs upon exceeding a critical threshold level. These threshold levels may vary widely between different organs in the same organism. In many cases, these unique features of mitochondrial genetics and the fact that also nuclear gene defects lead to mitochondrial diseases render the diagnostics a special challenge in human medicine. See also Genotype-Phenotype Relationships

Genetic Defects Causing Mitochondrial Disorders

  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

Traditionally, the term ‘mitochondrial disorders’ describes defects in the energy-providing apparatus of the mitochondrion, that is, the RC coupled to oxidative phosphorylation (OXPHOS). The biogenesis of four of the five OXPHOS enzyme complexes is under the control of the two genomes. Mitochondrial disorders can, therefore, be caused independently by mutations of either the mitochondrial or the nuclear DNA. Since the first description of mtDNA defects in 1988, a large number of point and length mutations in mtDNA have been reported, while mutations in nuclear genes encoding OXPHOS subunits were completely unknown. This situation changed markedly during the late 1990s: firstly, nuclear mutations observed in structural OXPHOS genes were published; secondly, mutations in genes indirectly affecting OXPHOS function were reported; thirdly, a growing number of nuclear gene defects involved in mitochondrial pathways which are not linked to the energy-production system became apparent. The term ‘mitochondrial disorders’ therefore comprises a highly diverse group of disorders, with a wide variety of inheritance pattern and clinical phenotypes. Examples of neurological manifestations are:

  • Stroke-like episodes

  • Seizures, myoclonus

  • Optic neuropathy

  • Sensorineural hearing loss

  • Ataxia

  • Ptosis, ophthalmoplegia

  • Developmental delay

  • Dementia

  • Dystonia

  • Myelopathy

  • Headache

  • Exercise intolerance, fatigability

  • Myopathy

Examples of systemic manifestations are:

  • Cardiomyopathy

  • Cardiac conduction defects

  • Pigmentary retinopathy

  • Cataracts

  • Diabetes mellitus

  • Hypoparathyroidism

  • Exocrine pancreatic dysfunction

  • Hepatopathy

  • Episodic nausea and vomiting

  • Intestinal pseudo-obstruction

  • Nephropathy

  • Sideroblastic anemia

  • Pancytopenia

  • Short stature

  • Metabolic acidosis

See also Genetic Disorders

Mutations of the mtDNA

Pathogenic mutation of the mitochondrial genome can be classified approximately into two main groups: first, single-base substitutions, including missense mutations within the 13 protein-encoding genes, and base substitutions within rRNA and tRNA genes, thereby globally affecting mitochondrial protein synthesis; second, large-scale rearrangements such as deletions, insertions or duplications. To date, approximately 100 different pathogenic mutations in the mitochondrial genome have been associated with human disorders. An up-to-date version of this steadily increasing list of mtDNA diseases is available through the internet database MITOMAP (see Table 1). As listed in the previous section, a wide variety of clinical phenotypes have been described in association with mtDNA defects (Table 1). In most of the cases, dysfunction of RC complexes has been documented, although a clear correlation between the biochemical defect and the clinical phenotype is lacking. A histopathological hallmark of mtDNA disorders, in particular of those caused by defects in mitochondrial tRNA genes, is the presence of so-called ragged red fibers (RRFs), which represent areas of mitochondrial proliferation in muscle biopsies.

Table 1. Genetic classification of mitochondrial disorders
 Disease genesCommon phenotype
  1. a

    Only the commonest gene mutations have been listed. A full list of known mtDNA mutations is available through MITOMAP.

adPEO: autosomal dominant PEO syndrome; COX: cytochrome c oxidase; CPEO: chronic progressive external ophthalmoplegia; KSS: Kearns–Sayre syndrome; LHON: Leber hereditary optic neuropathy; MELAS: mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MERRF: myoclonic epilepsy with ragged red fibers; MIDD: maternally inherited diabetes and deafness; MNGIE: neurogastrointestinal encephalomyopathy syndrome; mtDNA: mitochondrial deoxyribonucleic acid; NARP: neurogenic muscle weakness, ataxia and retinitis pigmentosa; rRNA: ribosomal ribonucleic acid; tRNA: transfer RNA.
Mitochondrial DNA  
Mutations in protein-coding genesaMTND1 G3460ALHON
 MTND6 G14459ALHON plus dystonia
 MTATP6 T8993CNARP, Leigh syndrome
 MTATP6 T9176GLeigh syndrome
Mutations in tRNA genesaMTTL1 (tRNALeu(UUR)) 3243GMELAS; MIDD; CPEO; MERRF
 MTTS1 (tRNASer(UCN)) 7445GSensorineural hearing loss
 MTTS1 (tRNASer(UCN)) 7472insCHearing loss, ataxia, myoclonus
 MTTS1 (tRNASer(UCN)) 7512CMERRF/MELAS overlap syndrome
Mutations in rRNA genesaMTRNR1 (12S rRNA) 1555GAminoglycoside-induced deafness
mtDNA rearrangementsSingle deletionCPEO
 Single deletionKSS
 Single deletion or duplicationPearson syndrome
Nuclear DNA  
Complex I genesNDUFS4Leigh-like syndrome
 NDUFS7Leigh syndrome
 NDUFS8Leigh syndrome
 NDUFS2Hypertrophic cardiomyopathy and encephalomyopathy
 NDUFV1Leukodystrophy and myoclonic epilepsy
Complex II genesSDHALeigh syndrome
‘Assembly’ genesSURF1Leigh syndrome + COX deficiency
 SCO2Hypertrophic cardiomyopathy
 SCO1Neonatal-onset hepatic failure and encephalopathy
 BCS1LEncephalo-, tubulo-, hepatopathy
mtDNA stability genesTMPOMNGIE
 SLC25A4adPEO (linked to chromosome 4q)
 DGUOKmtDNA depletion syndrome
 TK2mtDNA depletion syndrome
Other nuclear genesTIMM8A (DDP1)Mohr–Tranebjaerg syndrome
 SPG7 (paraplegin)Hereditary spastic paraplegia
 FRDA (frataxin)Friedreich ataxia
 OPA1Autosomal dominant optic atrophy
Diseases due to mutations in protein-encoding genes

Leber hereditary optic neuropathy (LHON) may serve as a paradigm for a missense mutation-mediated mitochondrial disease. Clinically, this disease results in a severe subacute and painless loss of central vision, abnormalities in color vision and bilateral atrophy of the optical nerve. For unknown reasons, the penetrance is much higher in males than in females. Three single mtDNA point mutations are designated ‘primary’ mutations, since each of them alone is able to cause LHON. These are the mutations located at nucleotide positions (nps) 11778 (in the MTND4 (NADH dehydrogenase 4) gene), 3460 (in the MTND1 (NADH dehydrogenase 1) gene) and 14484 (in the MTND6 (NADH dehydrogenase 6) gene). Together, they account for more than 90% of all LHON cases worldwide. Moreover, a G to A transition in the MTND6 gene (np 14459) has been found in patients suffering from LHON in association with dystonia. While the ‘primary’ LHON mutations are considered to be moderately deleterious (they are generally homoplasmic in affected individuals), the np 14459 mutation is disease-causing at relatively low levels of heteroplasmy. The np 14459 mutation also provides a good example of the phenotypic variability that can be produced as a heteroplasmic point mutation: atrophy of the optic nerve in np 14459 carriers is caused at low degrees of heteroplasmy, whereas the appearance of dystonia (a generalized movement disorder frequently associated with degeneration of basal ganglia) requires a higher concentration of mutated mtDNA.

Maternally inherited Leigh syndrome is a severe neurodegenerative disorder of childhood characterized by a progressive psychomotor retardation or regression, which can be caused by mtDNA mutations at np 8993 or np 9176 within the MTATP6 (ATP synthase 6) gene. Both mutations were found in variable degrees of heteroplasmy. At low levels the np 8993 mutation leads to the NARP syndrome (neurogenic muscle weakness, ataxia and retinitis pigmentosa); higher percentages of mutated mtDNA are associated with the severe and early-onset Leigh syndrome. The np 8993 and np 9176 mutations which affect the ATP synthase complex (complex V) only account for a small number of Leigh cases. The vast majority of Leigh cases are caused by nuclear-encoded defects of complex I, IV or the pyruvate dehydrogenase.

Furthermore, an increasing number of pathogenic mutations are found in genes encoding cytochrome b (MTCYB, cytochrome b) and subunits 1, 2 and 3 of the cytochrome c oxidase (COX; complex IV). Mutations in the MTCYB gene often cause isolated myopathies; mutations in mitochondrial MTCO1–3 genes appear to be associated with unrelated disorders such as myopathy, encephalomyopathy and sideroblastic anemia. In most cases, mutations in mtDNA-encoded COX subunits are sporadic.

Diseases due to mutations in tRNA and rRNA genes

Mutations in the mitochondrial protein synthesis genes can produce a complex array of symptoms. The most prominent example is the tRNALeu(UUR) (MTTL1, tRNA leucine 1) mutation at np 3243, originally described in a neurological syndrome, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). MELAS is the most common maternally inherited disorder. MELAS and the np 3243 mutation also exemplify how the same mtDNA mutation can give rise to different clinical phenotypes and, conversely, how a distinct clinical phenotype can be caused by different mutations. On the one hand, clinical symptoms found in association with np 3243 include cardiomyopathy, chronic progressive external ophthalmoplegia (CPEO), epilepsy, sensorineural hearing loss, progressive dementia and endocrine disorders, including diabetes mellitus. For example, the np 3243 mutation was found in association with a distinct subtype of diabetes, maternally inherited diabetes and deafness (MIDD), which accounts for 1.5% of the diabetic cases worldwide. On the other hand, several further nucleotide exchanges within the tRNALeu(UUR) (MTTL1) gene such as mutations at nps 3252, 3256, 3271 and 3291, or even mutations within protein-encoding genes, can lead to the clinical phenotype of MELAS. See also Deafness: Hereditary, and Diabetes: Genetics

Myoclonic epilepsy with ragged red fibers (MERRF) is a severe, multisystem disorder characterized by myoclonus, myoclonic epilepsy, ataxia, myopathy and the presence of ragged red fibers (RRFs) in the muscle biopsy. Other symptoms less frequently associated with this disease include cardiomyopathy, hearing loss, optic atrophy and seizures. The most common mtDNA gene defects associated with this phenotype are the mutations at np 8344 and np 8356 in the tRNALys gene (MTTK, tRNA lysine).

During the last decade of the twentieth century, genetic defects of mitochondrial tRNA genes emerged as a significant cause of a wide variety of clinical phenotypes. Mitochondrial tRNA mutations are commonly heteroplasmic. They frequently cause central nervous system abnormalities as well as mitochondrial myopathy with RREs, an association also known as mitochondrial encephalomyopathy. For example, mutations in the tRNSSer(UCN) (MTTS1, tRNA serine 1) are often found in association with sensorineural hearing loss (SNHL) either as an isolated symptom or in combination with other abnormalities such as ataxia, myoclonic epilepsy or myopathy. Other clinical phenotypes frequently caused by tRNA defects are cardiomyopathy, CPEO and endocrine abnormalities such as diabetes mellitus. Although the genes for tRNALeu(UUR) (MTTL1), tRNALys (MTTK), tRNAIle (MTTI) and tRNASer(UCN) (MTTS1) appear to represent mutational ‘hot spots’, pathogenic mutations can be found in almost every of the 22 tRNA genes. Among rRNA mutations, a homoplasmic base exchange at np 1555 in the mitochondrial 12S rRNA (MTRNR1) gene is the most frequent genetic defect, causing a nonsyndromic progressive form of deafness which occurs either spontaneously or can be induced by aminoglycosides. See also Deafness: Hereditary

Large-scale rearrangements of the mtDNA

Human diseases caused by mtDNA rearrangements are progressive external ophthalmoplegia (PEO), Kearns–Sayre syndrome (KSS), MIDD and Pearson marrow–pancreas syndrome. PEO is a relatively benign disorder characterized by weakness of the extraocular muscles and ptosis. PEO is also the leading symptom of KSS, a fatal, multisystemic disorder characterized by additional features such as retinitis pigmentosa, cerebellar syndrome, heart block and elevated cerebrospinal fluid. KSS and many cases of CPEO are sporadic and due to large, single deletions of the mtDNA, whereas the specific deletion varies among patients. Large-scale deletions (encompassing kilobases of mtDNA) usually remove tRNA genes, thereby resulting in a rapid decline of overall mitochondrial translation.

Nuclear-encoded mitochondrial disorders

Respiratory chain disorders

Numerous patients with enzyme deficiencies of one or more of the RC complexes have been reported. In most of these patients, the genetic cause is likely to be located on the nuclear DNA. Among patients with RC deficiencies, an isolated deficiency of complex I is most commonly observed. These patients often suffer from early-onset, multisystemic disorders such as the Leigh syndrome. As of 2002, pathogenic mutations in five of the 35 nuclear complex I genes have been identified (Table 1). Complex II deficiency is a very rare condition, corresponding to approximately 2% of RC deficiencies. Only one pathogenic mutation in the nuclear gene encoding the flavoprotein subunit of complex II has been reported in two siblings with Leigh syndrome. So far, sequence studies have failed to identify pathogenic mutations in nuclear genes coding for structural subunits of complex III and complex IV (COX). However, an increasing number of mutations in nuclear genes required for the assembly and maintenance of these complexes have now been associated with specific clinical phenotypes (Table 1): (1) A missense mutation in BCS1L (BCS1-like (yeast)) has been found in families suffering from early-onset tubulopathy, hepatopathy and encephalopathy. BCS1L codes for an inner membrane protein that is involved in the assembly of complex III. (2) Mutations in SURF1 (surfeit 1), which is involved in the assembly, stability or maintenance of complex IV (COX), appear to be specifically associated with Leigh syndrome in combination with COX deficiency. (3) Mutations in the human SCO2 (SCO cytochrome oxidase deficient homolog 2 (yeast)) gene, a mitochondrial copper chaperone mediating the delivery of copper ions to complex IV, cause a form of fatal, early-onset hypertrophic cardiomyopathy with encephalopathy and severe COX deficiency. (4) Mutations in SCO1 (SCO cytochrome oxidase deficient homolog 1 (yeast)) have been reported in a family with hepatopathy and ketoacidotic coma. (5) A missense mutation in the COX10 (COX10 homolog, cytochrome c oxidase assembly protein, heme A: farnesyltransferase (yeast)) gene (encoding heme A farnesyltransferase) was detected in a single case of leukodystrophy and proximal tubulopathy. See also Oxidative Phosphorylation System: Nuclear Genes and Genetic Disease

Disorders associated with reduced mtDNA stability

The stability and maintenance of integrity of the mtDNA is tightly regulated by nuclear-encoded factors, involved in mtDNA replication, repair or both. So-called disorders of nuclear–mitochondrial communication are caused by primary nuclear gene defects which subsequently cause mtDNA alterations such as large-scale deletions or even total loss of the mitochondrial genome (Table 1).

The most common disorder associated with multiple deletions of the mtDNA which follows a Mendelian inheritance is the autosomal dominant PEO syndrome (adPEO). Patients with adPEO are clinically characterized by ophthalmoparesis and exercise intolerance. variable proportions of multiple mtDNA deletions are found in tissues from these patients, with highest levels in brain and skeletal muscle. The disease appears to be genetically heterogeneous, since at least three distinct nuclear loci have been identified, on chromosomes 4q, 10q and 3p. Pedigrees linked to the adPEO locus on chromosome 4q have mutations within the SLC25A4 (solute carrier family 25 (mitochondrial carrier; adenine nucleotide translocator), member 4) gene. The SLC25A4 gene encodes the muscle- and heart-specific ATP/ADP nucleotide transporter, which is located in the mitochondrial inner membrane and regulates intramitochondrial ATP concentrations. Furthermore, the 10q-linked PEO1 (progressive external ophthalmoplegia 1) gene encodes a novel mitochondrial protein, twinkle, which shows striking similarity to phage T7 helicase and other hexameric ring helicases. The disease gene on 3p had not been identified as of 2002.

Two further diseases associated with autosomal inherited mtDNA alterations are the neurogastrointestinal encephalomyopathy syndrome (MNGIE) and the mtDNA depletion syndromes. The MNGIE syndrome is characterized by PEO, severe gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, RRFs and morphologically abnormal mitochondria. Multiple mtDNA alterations such as partial depletion, deletions or both have been observed. This autosomal recessive disease has been linked to mutations in ECGF1 (endothelial cell growth factor, platelet derived) a nuclear gene encoding thymidine phosphorylase. It has been speculated that dysfunction of ECGF1 alters cellular thymidine pools that are important for mtDNA maintenance, in particular mtDNA replication. The mtDNA depletion syndromes comprise a phenotypically heterogeneous group of autosomal recessive disorders characterized by tissue-specific reductions in the mtDNA copy number. In patients affected with the hepatocerebral form, the deoxyguanosine kinase gene (DGUOK) has been recently identified as the underlying disease gene. Furthermore, mtDNA depletion in association with severe, devastating myopathy is likely to be caused by mutations in the thymidine kinase-2 gene (TK2, thymidine kinase 2, mitochondrial). Together, these factors appear to play an important role in balancing the intramitochondrial deoxynucleoside triphosphate (dNTP) pool, which is important for the correct function of DNA polymerases and the fidelity of DNA synthesis. See also Mitochondrial DNA Repair in Mammals

Nuclear-encoded disorders not directly affecting OXPHOS function

At the end of the twentieth century, a number of Mendelian disorders became apparent that can be considered as mitochondrial diseases although the nuclear gene defects affect mitochondrial mechanisms other than OXPHOS function or mtDNA stability (Table 1). Friedreich ataxia is an autosomal recessive disease associated with cerebellar ataxia, peripheral neuropathy and hypertrophic cardiomyopathy. The mutant protein frataxin is located in the mitochondrial inner membrane and functions as a regulator of mitochondrial iron homeostasis. Although the specific role of frataxin is discussed controversially, frataxin deficiency leads to marked reductions in the activity of mitochondrial enzymes with Fe–S centers, that is, complex I and III and aconitase. Mohr–Tranebjaerg syndrome is an X-linked neurodegenerative disorder characterized by sensorineural hearing loss, dystonia, dementia and optic atrophy. It is caused by mutations in the TIMM8A (translocase of inner mitochondrial membrane 8 homolog A (yeast)) gene which encodes an evolutionarily conserved small protein, DDP1 (deafness-dystonia peptide 1), located in the mitochondrial intermembrane space. Functional information derived from its yeast homolog, Tim8, together with recent studies in the mammalian system suggest DDP1 to be involved in the import of inner membrane proteins such as Tim23 which plays an essential role in the import of nuclear-encoded mitochondrial precursor proteins. Loss of function of DDP1 might therefore result in defective mitochondrial biogenesis leading to severe pleiotropic mitochondrial dysfunction. Hereditary spastic paraplegia (HSP) describes a genetically heterogeneous group of disorders comprising autosomal dominant, autosomal recessive and X-linked forms. Patients suffering from HSP present with progressive weakness and spasticity of the lower limbs; mental retardation, peripheral neuropathy, ataxia and optic atrophy or deafness may also be present. An autosomal recessive form of HSP linked to chromosome 16q is caused by mutations in the SPG7 (spastic paraplegia 7, paraplegin (pure and complicated autosomal recessive)) gene. The gene product, paraplegin, shows homology to mitochondrial ATP-dependent proteases (AAA-proteases) of yeast which are involved in the quality control of mitochondrial inner membrane proteins. Finally, a dominantly inherited form of optic atrophy has been linked to the OPA1 (optic atrophy 1 (autosomal dominant)) gene, whose protein product belongs to the dynamin family and may be involved in the control of mitochondrial morphology. See also Deafness: Hereditary, Eye Disorders: Hereditary, Friedreich Ataxia, Iron Metabolism: Disorders, Yeast as a Model for Human Diseases, Protein Transport, and Protein Degradation and Turnover

Disorders related to other mitochondrial pathways

Although mitochondrial disorders are traditionally referred to as defects directly or indirectly affecting the OXPHOS system, a substantial number of human disorders are caused by defects of intermediate pathways located in mitochondria. These are in particular defects of fatty acid transport into mitochondria, defects of fatty acid degradation, amino acid degradation, ketone synthesis, pyruvate oxidation and defects of Krebs cycle and urea cycle enzymes (Table 2). A wide variety of clinical phenotypes are associated with these disorders, ranging from severe, early-onset and life-threatening phenotypes such as hypertrophic cardiomyopathy to late-onset and milder forms involving rhabdomyolysis or fasting intolerance. In contrast to mitochondrial- or nuclear-encoded OXPHOS disorders, for some of these metabolic disorders a therapy is available. For example, patients with primary systemic carnitine deficiency can be substituted with carnitine; medium-chain acyl-CoA deficiency (MCAD; a disorder of fatty acid degradation) can be treated by avoiding prolonged fasting periods and carbohydrate-rich feeding. Moreover, many of these metabolic defects can be readily diagnosed or followed up by quantification of carnitine or amino acid levels using tandem mass spectrometry. In particular, tandem mass spectrometry is already used for screening of inherited metabolic diseases in newborn infants. See also Lysosomal Storage Disorders: Gene Therapy, and Metabolism: Hereditary Errors

Table 2. Biochemical classification of mitochondrial diseases (See Phenylketonuria.)
CPT I, CPT II: carnitine-palmitoyl-transferase I and II; GA I, GA II: glutaric aciduria type I and II; HHH: hyperornithinemia-hyperammonemia-homocitrullinuria; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; IVA: isovaleric aciduria; LCAD: long-chain acyl-CoA; LCHAD: long-chain 3-hydroxy-acyl-CoA dehydrogenase; MADD: multiple acyl-CoA dehydrogenase; MCAD: medium-chain acyl-CoA; MSUD: maple syrup urine disease; OCT: ornithine carbomoyl-transferase; PDH: pyruvate dehydrogenase; SCAD: short-chain acyl-CoA; VLCAD: very long chain acyl-CoA.
Respiratory chainComplex I (NADH-ubiquinone reductase) deficiency
 Complex II (succinate-ubiquinone reductase) deficiency
 Complex III (ubiquinol-cytochrome c reductase) deficiency
 Complex IV (cytochrome c oxidase) deficiency
 Multiple respiratory chain deficiencies
Oxidation-phosphorylation coupling Fatty acid degradationComplex V (ATP synthase) deficiency
 Carnitine transporter defect (primary systemic carnitine deficiency)
 SCAD deficiency
 MCAD deficiency
 LCAD deficiency
 VLCAD deficiency
 LCHAD deficiency
 Trifunctional protein deficiency
 MADD deficiency
 Carnitine/acylcarnitine translocase deficiency
 CPT I deficiency
 CPT II deficiency
 2,4-Dienoyl-CoA-reductase deficiency
Amino acid metabolismGA I
 HMG-CoA lyase deficiency
 IVA 3-Hydroxyisobutyryl-CoA deacylase deficiency
 β-Ketothiolase deficiency
 3-Methylcrotonyl-CoA carboxylase deficiency
 3-Methylglutaconyl-CoA hydratase deficiency
 Holocarboxylase synthetase deficiency
 Methylmalonic aciduria - mutase deficiency
 B12 defect + homodystinuria
 Propionic aciduria
 OCT deficiency
 Argininosuccinate lyase deficiency
 Arginase deficiency
 HHH syndrome
PDH componentsPyruvate dehydrogenase (E1) deficiency
 Dihydrolipoamide acetyl transferase (E2) deficiency
 Dihydrolipoamide dehydrogenase (E3) deficiency
 Protein X deficiency
 Phospho-E phosphatase deficiency
Citric acid cycleAlpha-ketoglutarate dehydrogenase complex deficiency
 Fumarase deficiency
 Aconitase deficiency


  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

Knowledge about genetic causes of mitochondrial disorders and the functional consequences of distinct genetic defects has been steadily increasing. However, the molecular basis of the majority of autosomal recessive OXPHOS disorders in the pediatric population remains unknown. In particular, detailed functional insights into numerous proteins involved in the regulation of mitochondrial transcription, translation, import, sorting and assembly are still rather scanty. The final goal of investigating the genetic and functional causes of mitochondrial disorders is the prevention or treatment of these mostly devastating, and often fatal, inborn errors of metabolism. Of great importance has been the development of reliable molecular prenatal diagnosis for increasing numbers of families affected by nuclear DNA mutations. Furthermore, the generation of animal studies will help to study disease pathomechanisms and may be also used for therapeutic intervention studies. See also Mitochondrial Proteome: Origin

Further Reading

  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links

Web Links

  1. Top of page
  2. Introduction
  3. Mitochondrial Pathways
  4. Mitochondrial Genetics
  5. Genetic Defects Causing Mitochondrial Disorders
  6. Conclusions
  7. See also
  8. Further Reading
  9. Web Links
  • MITOMAP: A Human Mitochondrial Genome Database. The database comprises a compendium of polymorphisms and mutations of the human mitochondrial DNA. Clinical phenotypes and functional descriptions are provided via useful links on the Web
  • MITOP: Database for mitochondria-related genes, proteins and diseases. MITOP project is supported by a German Human Genome Project and combines all relevant information concerning genetic, functional and human-pathological aspects of the central role of mitochondria in the organism, with an emphasis on nuclear encoded proteins
  • MitoNet: This is a network of competence gathering physicians and scientists in order to improve research, diagnostics and therapy on/of ‘mitochondrial disorders’. MitoNet gives general information on mitochondrial disorders, supports specific patient groups, offers the expert knowledge to the medical society and supports the collaboration between clinic and research