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Acta Myol. 2009 July; 28(1): 16–23.
PMCID: PMC2859630

Mitochondrial disorders of the nuclear genome



Mitochondrial myopathies are regulated by two genomes: the nuclear DNA, and the mitochondrial DNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mitochondrial DNA, a new field of investigation is that of syndromes due to mutations in the nuclear DNA. These latter disorders have mendelian inheritance.


Three representative cases have been selected: one with COX deficiency and a Leigh syndrome due to a SURF1 gene mutation, one due to a defect of Coenzyme Q synthesis and one with dominant optic atrophy due to a mutation in the OPA1 gene.


Future developments will show that many neurodegenerative disorders are due to mutations of nuclear genes controlling mitochondrial function, fusion and fission.

Keywords: SURF1, ataxia, optic atrophy


Production of energy in mitochondria, by means of oxidative phosphorylation, strictly depends upon factors which are encoded both by the mitochondrial DNA (mtDNA) and the nuclear genome (nDNA). Respiratory chain complexes are formed, for the most part by subunits of nuclear origin, as are several indispensable complex-assembling proteins. Accurate replication and efficient maintenance of mtDNA are also essential for the respiratory chain to function properly.

Many metabolic processes, distinct from ATP production, are fulfilled in mitochondria: for instance, important steps of metal cation metabolism take place in the mitochondrial matrix. Furthermore, mitochondria actively fuse and divide, and move interacting with the cytoskeleton. All these functions require the expression of nuclear genes. Mitochondrial disorders caused by nDNA defects have been the object of increasing attention in the past few years, establishing themselves as an important and relatively prevalent group of pathologies, and challenging the relevance of disease caused by inherited mutations of mtDNA itself.

Disorders involving mtDNA replication are referred to as “intergenomic signalling defects” (1), and may be divided into two main categories: qualitative defects, i.e., multiple mtDNA deletions, and quantitative defects, i.e., mtDNA depletion syndromes. Other relevant genes include those for respiratory chain subunits and their ancillary proteins, as well as those for enzymes performing critical steps in metabolic pathways, or proteins involved in mediating mitochondrial fusion and fission.

Genes and syndromes

Major nuclear genes giving rise to mitochondrial disease have been reviewed, with reference to pathophysiologic mechanisms and clinical phenotypes (Table (Table1).1). Three cases are reported as an example of the clinical spectrum of these disorders.

Table 1
Classification of mitochondrial disorders caused by nuclear genes.

Multiple mtDNA deletions

The first nDNA mutations to be associated with secondary multiple deletions of mtDNA were described due to a thymidine phosphorylase gene (TP) defect by Nishino et al. in 1999 (2). TP does not localize in mitochondria, but it is functionally related to mtDNA replication, as its impairment alters the composition of the nucleotide pool within the mitochondrial matrix. The resulting phenotype is Mitochondrial Neuro-Gastro-Intestinal leukoEncephalopathy (MNGIE), an autosomal recessive (AR) disease of young adulthood which severely reduces life expectancy, mostly due to intestinal malabsorption and cachexia. External ophthalmoplegia and neuropathy may also be present (3).

In the following years, other nuclear genes were found to be mutated in patients affected by progressive external ophthalmoplegia with a mendelian pattern of inheritance. Evidence was produced in animal models that defective nucleotide exchange across the mitochondrial membrane eventually leads to damage of mtDNA, possibly through a mechanism which involves production of reactive oxygen species and oxidative stress. These experiments employed adenine nucleotide translocator 1 (ANT1) null mice (4). The corresponding human gene, when altered, causes adult-onset autosomal dominant progressive external ophthalmoplegia (adPEO) (5).

The same clinical syndrome may similarly originate from mutations in TWINKLE. The protein product of this gene was found to be a helicase, to co-localize with mtDNA, and to lead to accumulation of multiple mtDNA deletions when altered (6, 7). More recently, an additional phenotype, Infantile Onset SpinoCerebellar Ataxia (IOSCA), has been repoted to be caused by alterations of the Twinkle helicase or of its splicing variant Twinky. This severe disease is the only AR phenotype to be associated with TWINKLE mutations (8).

Mutations in the POLG gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase (pol-γ), have been related to a wide variety of autosomal disorders, inherited both in a dominant and recessive fashion. Structural defects in pol-γ lead to age-related accumulation of multiple mtDNA deletions. Less frequently, similar or identical mutations may alternatively cause mtDNA depletion, and thus more severe, early-onset phenotypes. Molecular mechanisms underlying such variability have not yet been completely elucidated (9).

The first phenotype to be described in association with POLG mutations was again autosomal dominant AD-PEO (10), followed by other AD syndromes such as parkinsonism and premature ovarian failure (11), and by AR disorders characterized by sensory-ataxic neuropathy and dysarthria together with external ophthalmoplegia (SANDO) (12). AR-inherited POLG mutations also cause Alpers syndrome, a severe paediatric hepato-encephalopathy. Such phenotypes present critical mtDNA depletion from birth, rather than a slow accumulation of deletions over the years, suggesting a greater functional impairment of the polymerase (13).

mtDNA depletion

Myopathic and hepato-cerebral syndromes are the main phenotypes to be observed in patients with consistent quantitative reduction of mtDNA. These groups of AR disease resemble multiple deletion syndromes in that they are caused by alterations in deoxyribonucleotide triphosphate metabolic pathways, but are usually severe and present earlier in life.

Myopathic forms are related to mutations in TK2, which encodes for thymidine kinase 2, and show an AR pattern of inheritance (14,15). In most cases, a slowly progressive mitochondrial myopathy develops, but the clinical spectrum for this gene has recently spanned to include spinal muscular atrophy and severe congenital myopathy (16, 17).

Encephalomyopathic variants, reminiscent of Leigh syndrome, were found in patients with SUCLA2 homozygous mutations, who carried a subsequent defect of the beta-subunit of the ADP-forming succinyl-CoA synthase (SCS-A) (18).

Deoxyguanosine kinase deficiency, arising from mutations in DGUOK (19), and, as very recently discovered, MPV17 mutations (20), are the basis for hepato-cerebral degenerative syndromes with mtDNA depletion. From a clinical standpoint, these disorders can be grouped under the eponym of Alpers syndrome, together with the afore-mentioned severe varieties of pol-γ deficiencies.

Respiratory chain (RC) subunit defects

More than 70 out of >90 polypeptides which constitute the RC are encoded by the nucleus. Many of the respective genes have been shown to be mutated in human diseases.

Complex I is that most frequently involved in these pathologies. Several culprit genes have been identified: NDUSF2, NDUSF4, NDUSF6, NDUSF7, NDUSF8, NDUFV1 and NDUFV2 (21, 22), but they are not sufficient to explain all cases of complex I deficiency of mendelian inheritance, therefore leaving space for speculation about possible, as yet unidentified, ancillary protein defects.

Complex II deficiency is a rare cause of mitochondrial encephalomyopathy, caused by homozygous mutations in SDHA (23). This gene encodes for one of the four subunits of complex II, which is the smallest complex of the RC, and the only one to be entirely nuclear in origin. Mutations of the other three subunits have been associated with familiar endocrine tumours (24).

Defects of ancillary proteins

Many cases of specific RC complex deficiency, asrevealed by biochemical assays, show a quantitative reduction or structural disruption of the affected complex, which cannot be explained by mutations in mtDNA or nDNA encoded subunits. This scenario is typical of assembly protein defects, many of which have already been identified.

Complex III deficiencies are commonly caused by a defect of cytochrome b, which is encoded by mtDNA. However, some patients with complex III deficiency and mitochondrial encephalopathy have a normal cytochrome b. These particular patients were found to carry a point mutation in the ancillary protein gene BCS1L (25). Phenotype is severe with features of multisystemic failure, as summarized by the acronym GRACILE (Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactacidosis, Early death) (26).

Deficiency of cytochrome C oxidase (COX, complex IV) is one of the most frequent causes of Leigh syndrome. There are no known mutations of nuclear genes encoding for COX subunits, as autosomal COX deficiency seems to be entirely due to lack of assembly proteins. SURF1 was the first candidate nuclear gene to be connected to COX-deficient encephalomyopathy, as illustrated in Case 1 (27, 28). Other genes were subsequently linked to COX deficiency, notably SCO2 and COX15. Clinical features were comprehensive of encephalomyopathy, early-onset fatal hypertrophic cardiomyopathy, neuropathy (2931). Both SCO2 and COX15 play relevant roles in the regulation of cytochrome C prosthetic groups, respectively, binding copper and heme iron (32, 33).

Case 1: Childhood encephalomyopathy with COX deficiency, ataxia, muscle wasting, and mental impairment (27). Case 1 refers to a boy with consanguineous parents (third cousins) born after an uneventful pregnancy and delivery. Psychomotor development delay, muscle hypotonia and gait disturbances were evident at age 2 years. At the time of muscle biopsy (age 8 years), the boy presented hypotonia, muscle hypotrophy, axial and limb ataxia, and was unable to walk unassisted. Mental impairment was mild. Ocular motility was impaired with a bilateral abduction defect resulting in a converging squint. His face and lower extremities were hairy. Electromyography (EMG) showed myopathic features, and a right bundle branch block was found on electrocardiography. He had a rapid right frontoparietal rhythm on electroencephalography and delayed brainstem evoked potentials.

Muscle biopsy demonstrated many atrophic vacuolated fibres with numerous oil red O positive lipid droplets, and a faint histo-enzymatic reaction for COX. COX activity was decreased to 7% of the normal mean in muscle homogenate, while other mitochondrial enzymes were normal. A homozygous mutation in SURF1 was subsequently demonstrated.

Complex V, i.e., the F0F1 ATPase, has also been found to be a cause of encephalomyopathy due to a mutation in an assembly protein gene, ATP12 (34). As seen with complex IV, no nuclear-encoded subunit defects are known.

Primary Coenzyme Q defect

To be included in this group are the defects of coenzyme Q (CoQ) synthesizing proteins (Case 2), which have only very recently started to be genetically defined. Inheritance is AR and clinical characteristics are heterogeneous, ranging from encephalomyopathy, to renal tubulopathy and ataxic neuropathy. Mutations have been described in the para-hydroxybenzoate-polyprenyl transferase gene COQ2 -as exemplified in Case 2 (35, 36) and in PDSS2, which encodes for subunit 2 of decaprenyl-diphosphate-synthase (37).

Case 2: Infantile encephalomyopathy, nephrotic syndrome CoQ deficiency. Patient 2 refers to a boy born with consanguineous parents (first cousins) of North African origin, after an uneventful pregnancy and delivery. At age 2 months, nystagmus was noted. At age 12 months, the boy developed a severe, corticosteroid-resistant nephrotic syndrome. Renal biopsy revealed focal and segmental glomerulosclerosis. Acquisition of developmental milestones was slightly delayed, and a mild hypotonia was evident on neurologic examination. Fundoscopy revealed optic atrophy. Plasma creatine kinase and lactate were normal. Brain magnetic resonance imaging (MRI), echocardiography and brainstem auditory evoked potentials were normal. Visual evoked potentials showed an altered retinocortical transmission, and an electroretinogram indicated rod cone retinopathy. In the following months, a deterioration was observed both in renal function, requiring dialysis, and in brain function: at age 18 months, the boy lost the ability to walk and stand unassisted. Cerebral spinal fluid lactate, serum amino acids and urinary organic acids were within normal limits. He developed frequent vomiting, psychomotor regression and focal status epilepticus. A new brain MRI showed diffuse cerebral atrophy, mild cerebellar atrophy and lesions in the cingulate cortex and subcortical area. At the age when muscle biopsy was performed (22 months) the patient had developed right hemiplegia and swallowing difficulties. The muscle biopsy had an essentially normal morphology. Subsarcolemmal accumulation of succinate dehydrogenase stain was evident in some fibers. Activity of complex II + III, which depends on coenzyme Q (CoQ), was decreased. Subministration of CoQ resulted in prompt and dramatic improvement of muscle tone and strength, remission of vomiting and myoclonus, and regain of the ability of standing and walking unassisted, as well as of other developmental milestones that had been previously lost. Unfortunately, CoQ therapy was not sufficient to correct renal dysfunction, and the boy remained dependent on dialysis. A homozygous missense mutation was identified in COQ2 by analysis of the eight known human genes (COQ1-8) which encode for CoQ biosynthetic proteins. An A→G transition at a highly conserved position (nucleotide 890) caused amino acid 297 to change from tyrosine to cysteine.

Defects of metal cation metabolism

The mitochondrial matrix is a major site for heme and [Fe-S] cluster synthesis. When these metabolic pathways are disrupted, damage is caused to the cell not only by the lack of prosthetic groups for several mitochondrial and non-mitochondrial proteins, but also by the ungovernable production of reactive oxygen species which the free forms of metal cations catalyze (38).

The first step in heme synthesis, i.e., condensation between glycine and succinyl-CoA resulting in δ-aminolevulinic acid (ALA), is mediated by δ-aminolevulinic acid synthetase (ALAS) (39). The erythroid isoform of ALAS is encoded by ALAS2, and its deficiency causes X-linked sideroblastic anaemia (40). It is interesting to note that no neuropathy is observed in this disease, as the neural isoform of ALAS is encoded by a distinct gene, ALAS1 (41). X-linked sideroblastic aneamia with ataxia, on the other hand, is caused by an alteration of a transporter protein of the ATP-binding cassette superfamily (ABCB7 mutations): [Fe-S] cluster transportation from the mitochondrial matrix to the cytosol. If this is impaired, leads to iron accumulation in mitochondria and multisystemic dysfunction of iron metabolism (42).

Metal cation accumulation and consequent oxidative damage, mainly within tissues of high mitochondrial content, such as CNS and nerve, is widely thought to be a pathogenetic feature common to many neurodegenerative diseases. Friedreich’s ataxia is the most frequent AR hereditary ataxia, and is caused by intronic GAA repeats in the gene for frataxin, FRDA (43). Mitochondrial localization of frataxin (44) and iron overload in afflected tissues, such as nerve and myocardium (45), point to a deficit in mitochondrial trafficking of iron atoms. Furthermore, the partial benefit obtained with free-radical scavengers such as idebenone (46) would suggest an increased oxidative stress associated with iron overload in Friedreich’s ataxia pathogenesis, although the specific role of frataxin in the process has not yet been univocally defined.

Friedreich’s ataxia is a model for the crucial role of mitochondria in neurodegeneration. Similar mechanisms may have a role in the genesis of other, far more prevalent degenerative diseases (such as Alzheimer’s and Parkinson’s) which affect a large part of the senile population (47, 48). Mitochondrial dysfunction enhances production of free radicals, the immediate consequences of which are mtDNA replication errors and/or direct mtDNA damage, leading to further mitochondrial dysfunction. This vicious cycle may be relevant to the physiologic process of ageing itself, even if some experimental findings do not indicate this mechanism (49).

Defects of mitochondrial motility, fusion and fission

Mitochondria, in no different way than other intracellular organelles, are known to exert a dynamic relationship with the cytoskeleton, which allows them to move within the cell. Balance of fusion and fission forces determines morphologic and functional aspects of mitochondria (50). A kinesin, KIF5A, is altered in a pure form of hereditary spastic paraplegia (51), while mutations of dynamin related GTPase OPA1 provoke AD optic nerve atrophy, a mitochondrial cause of vision loss distinct from maternally inherited Leber’s optic neuropathy (52). A peculiar association of AD optic atrophy with neuropathy has been proposed in Case 3 (53). MFN2 (mitofusin 2) mutations, on the other hand, produce the hereditary sensorimotor neuropathy classified as CMT-2A, caused by a disturbance of mitochondrial fusion pathways (54).

Case 3: Autosomal dominant optic atrophy and neuropathy (53). A 46-year-old female complained of slowly progressive visual loss and dyschromatopsia since 10 years of age. She also complained of nocturnal distal paresthesias in the four limbs. She had optic atrophy (Fig. (Fig.1)1) both upon fundoscopic examination and brain MRI (Fig. (Fig.2).2). EMG showed a severe sensory-motor axonal neuropathy. The patient’s sister, aged 45 years, also complained of visual loss, also present in several other members of her family with a pattern suggesting an autosomal dominant inheritance.

Figure 1
Case 3: Diffuse optic atrophy on fundus photograph.
Figure 2
Case 3: Brain MRI showing bilateral optic nerve atrophy.

Muscle biopsy was performed, showing neurogenic atrophy and aggregates of abnormally-shaped mitochondria on electron microscopy (Fig. (Fig.3).3). Molecular analysis of the OPA1 gene showed a new 38 base pair deletion in the junction between exon and intron 14, causing a splice site defect.

Figure 3
Case 3: Muscle biopsy showing atrophic fibres on Haematoxylin-Eosin stain (A), mini fibre type-grouping on acid ATP-ase (B), and aggregates of abnormally-shaped mitochondria on electron microscopy (C).

It was not until very recently that a disease, due to mitochondrial fission disturbances, was demonstrated. A dominant-negative mutation in dynamin-like protein 1 gene (DLP1) was found in a girl with microcephaly, optic atrophy and lactic acidosis, and a defect in fission capabilities both of mitochondria and peroxisomes was noted (55).


The cases reported here illustrate the wide clinical spectrum of mitochondrial disorders caused by nuclear genes. Diagnostic suspicion is arisen by a multisystemic pattern of involvement, typical of mitochondriopathies, in the presence of apparent mendelian inheritance. Reaching a correct diagnosis may have remarkable therapeutic implications, as emphasized in Case 2.

New syndromes and mutations are being described with growing frequency, but we are not yet able to quantify the overall impact, in terms of incidence, of mitochondrial disorders depending on the nuclear genome. While epidemiologic studies of primary mtDNA alterations have produced figures of a minimum 1/5000 prevalence (56, 57), the spectrum of these disorders has not yet been systematically defined from an epidemiological standpoint. Yet, as knowledge increases (and consequentially as more cases are correctly diagnosed), these disorders might be recognized as an important group of mitochondrial diseases, imposing a heavy burden on the community, both from a sanitary and social point of view. Further insight into the molecular mechanisms should provide hope for new therapeutic strategies to be experimented and applied.


Study conducted with support of grants from Telethon-Italy (GTB07001) and EuroBioBank network partner of Treat-NMD Neuromuscular Network (6th framework programme).


1. DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromusc Disord 2005;15:276-86. [PubMed]
2. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689-92. [PubMed]
3. Hirano M, Nishino I, Nishigaki Y, et al. Thymidine phosphorylase gene mutations cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Intern Med 2006;45:1103. [PubMed]
4. Esposito LA, Melov S, Panov A, et al. Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci USA 1999;96:4820-5. [PubMed]
5. Kaukonen J, Juselius JK, Tiranti V, et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 2000;289:782-5. [PubMed]
6. Spelbrink JN, Li FY, Tiranti V, et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 2001;28:223-31. [PubMed]
7. Lewis S, Hutchison W, Thyagarajan D, et al.. Clinical and molecular features of adPEO due to mutations in the Twinkle gene. J Neurol Sci 2002;201:39-44. [PubMed]
8. Nikali K, Suomalainen A, Saharinen J, et al. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet 2005;14:2981-90. [PubMed]
9. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006;129:1674-84. [PubMed]
10. Van Goethem G, Dermaut B, Lofgren A, et al. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 2001;28:211-12. [PubMed]
11. Luoma P, Melberg A, Rinne JO, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004;364:875-82. [PubMed]
12. Van Goethem G, Martin JJ, Dermaut B, et al. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromusc Disord 2003;13:133-42. [PubMed]
13. Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol 2004;55:706-12. [PubMed]
14. Saada A, Shaag A, Mandel H, et al. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 2001;29:342-4. [PubMed]
15. Mancuso M, Filosto M, Bonilla E, et al. Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene. Arch Neurol 2003;60:1007-9. [PubMed]
16. Oskoui M, Davidzon G, Pascual J, et al. Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch Neurol 2006;63:1122-6. [PubMed]
17. Mancuso M, Salviati L, Sacconi S, et al. Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. Neurology 2002;59:1197-202. [PubMed]
18. Elpeleg O, Miller C, Hershkovitz E, et al. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 2005;76:1081-6. [PubMed]
19. Mandel H, Szargel R, Labay V, et al. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 2001;29:337-41. [PubMed]
20. Spinazzola A, Viscomi C, Fernandez-Vizarra E, et al. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 2006;38:570-5. [PubMed]
21. Ugalde C, Janssen RJ, van den Heuvel LP, et al. Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency. Hum Mol Genet 2004;13:659-67. [PubMed]
22. Kirby DM, Salemi R, Sugiana C, et al. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest 2004;114:837-45. [PMC free article] [PubMed]
23. Bourgeron T, Rustin P, Chretien D, et al. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11:144-9. [PubMed]
24. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49-54. [PubMed]
25. Fernandez-Vizarra E, Bugiani M, Goffrini P, et al. Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. Hum Mol Genet 2007;16:1241-52. [PubMed]
26. Visapaa I, Fellman V, Vesa J, et al. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 2002;71:863-76. [PubMed]
27. Angelini C, Bresolin N, Pegolo G, et al. Childhood encephalomyopathy with cytochrome c oxidase deficiency, ataxia, muscle wasting, and mental impairment. Neurology 1986;36:1048-52. [PubMed]
28. Pequignot MO, Dey R, Zeviani M, et al. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. Hum Mutat 2001;17:374-81. [PubMed]
29. Papadopoulou LC, Sue CM, Davidson MM, et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 1999;23:333-7. [PubMed]
30. Jaksch M, Horvath R, Horn N, et al. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 2001;57:1440-6. [PubMed]
31. Antonicka H, Mattman A, Carlson CG, et al. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 2003;72:101-14. [PubMed]
32. Jaksch M, Paret C, Stucka R, et al. Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum Mol Genet 2001;10:3025-35. [PubMed]
33. Barros MH, Carlson CG, Glerum DM, et al. Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O. FEBS Lett 2001;492:133-8. [PubMed]
34. De Meirleir L, Seneca S, Lissens W, et al. Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 2004;41:120-4. [PMC free article] [PubMed]
35. Salviati L, Sacconi S, Murer L, et al. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 2005;65:606-8. [PubMed]
36. Quinzii C, Naini A, Salviati L, et al. A Mutation in Para-Hydroxybenzoate-Polyprenyl Transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 2006;78:345-9. [PubMed]
37. Lopez LC, Schuelke M, Quinzii CM, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 2006;79:1125-9. [PubMed]
38. Napier I, Ponka P, Richardson DR. Iron trafficking in the mitochondrion: novel pathways revealed by disease. Blood 2005;105:1867-74. [PubMed]
39. Kikuchi G, Shemin D, Bachmann BJ. The enzymic synthesis of delta-aminolevulinic acid. J Biol Chem 1958;233:1214-19. [PubMed]
40. Cotter PD, Baumann M, Bishop DF. Enzymatic defect in “X-linked” sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency. Proc Natl Acad Sci USA 1992;89:4028-32. [PubMed]
41. Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 1997;89:1-25. [PubMed]
42. Shimada Y, Okuno S, Kawai A, et al. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. J Hum Genet 1998;43:115-22. [PubMed]
43. Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271:1423-7. [PubMed]
44. Campuzano V, Montermini L, Lutz Y, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997;6:1771-80. [PubMed]
45. Puccio H, Simon D, Cossee M, et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 2001;27:181-6. [PubMed]
46. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, et al. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet 1999;354:477-9. [PubMed]
47. Trushina E, McMurray CT. Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 2007;145:1233-48. [PubMed]
48. Mancuso M, Coppede F, Migliore L, et al. Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimer Dis 2006;10:59-73. [PubMed]
49. Trifunovic A, Larsson NG. Mitochondrial dysfunction as a cause of ageing. J Intern Med 2008;263:167-78. [PubMed]
50. Bereiter-Hahn J, Voth M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech 1994;27:198-219. [PubMed]
51. Fichera M, Lo Giudice M, Falco M, et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004;63:1108-10. [PubMed]
52. Delettre C, Lenaers G, Griffoin JM, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000;26:207-20. [PubMed]
53. Spinazzi M, Cazzola S, Bortolozzi M, et al. A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. Hum Mol Genet 2008;17:3291-302. [PubMed]
54. Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004;36:449-51. [PubMed]
55. Waterham HR, Koster J, van Roermund CW, et al. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 2007;356:1736-41. [PubMed]
56. Schaefer AM, Taylor RW, Turnbull DM, et al. The epidemiology of mitochondrial disorders: past, present and future. Biochim Biophys Acta 2004;1659:115-20. [PubMed]
57. Skladal D, Bernier FP, Halliday JL, et al. Birth prevalence of mitochondrial respiratory chain defects in children. J Inherit Metab Dis 2000;23;138.

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