Human Molecular Genetics, 2001, Vol. 10, No. 20 2277-2284
© 2001 Oxford University Press
Nuclear genetic defects of oxidative phosphorylation
Montreal Neurological Institute and Department of Human Genetics, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada
Received July 12, 2001; Accepted July 25, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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ATP generated by oxidative phosphorylation is necessary for the normal function of most cells in the body. Partial deficiencies in this system are an important cause of a large and diverse group of multisystem disorders. As both the nuclear and mitochondrial genomes encode structural components of the enzyme complexes of the oxidative phosphorylation system, the disorders can be transmitted either in a Mendelian fashion or maternally, or can occur as sporadic cases. Over the last 12 years more than 100 mutations have been uncovered in mtDNA, mostly associated with disease in the adult population. Recently, much attention has turned to the investigation of the nuclear oxidative phosphorylation gene defects. The majority of these are inherited as autosomal recessive traits, producing severe, and usually fatal disease in infants. Adult-onset Mendelian oxidative phosphorylation diseases, which can be inherited as autosomal recessive or dominant traits, have a milder phenotype, and most are associated with multiple mtDNA deletions. Approximately 20 different nuclear gene defects have now been identified in genes coding for structural components of the complexes, assembly/maintenance factors and factors necessary for the maintenance of mtDNA integrity. Some clear genotype–phenotype associations have emerged, and there is an unexpected link between some structural gene mutations and rare cancers, implicating mitochondria as oxygen sensors in the hypoxia response.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Deficiencies in oxidative phosphorylation are associated with a diverse array of multisystem disorders that are often referred to as mitochondrial encephalomyopathies because of the prominent involvement of the nervous system and striated muscle. The oxidative phosphorylation system is composed of the four enzyme complexes (complexes I–IV) that make up the mitochondrial respiratory chain, and the ATP synthase complex (complex V), which uses the energy generated by electron transport along the respiratory chain to produce ATP. The subunits of the five enzyme complexes are encoded in both the nuclear and mitochondrial genomes; of the 82 structural subunits, 13 are encoded in mtDNA. In addition to the structural components of the oxidative phosphorylation system, a large number of proteins that have only been partially characterized are involved in its assembly and maintenance. Half of the known mitochondrial proteins in the yeast Saccharomyces cerevisiae are involved in some aspect of mitochondrial biogenesis (1).
Once thought to be very rare, it is now clear that oxidative phosphorylation deficiencies are an important cause of a wide range of neurological, neuromuscular, cardiac and endocrine disorders, and even some cancers. The minimum prevalence of these diseases has been estimated at 1:8500 in a Caucasian population in northern England (2). Mutations in mtDNA are the most frequent cause of mitochondrial disease in adults and over the past 12 years more than 100 such pathogenic mutations have been identified (mtDNA) (Mitomap: http://www.gen.emory.edu/mitomap.html). In the pediatric population, most oxidative phosphorylation disorders are transmitted as autosomal recessive traits, usually with severe phenotypes and a fatal outcome. Mendelian oxidative phosphorylation disorders have also been described in adults, most of which result in a progressive loss of the integrity of mtDNA. Using a variety of approaches (linkage analysis, candidate genes, functional complementation) the nuclear gene defects in these disorders are beginning to be unraveled, and work has started on the mechanisms of pathogenesis. In this article, I review the recent progress in this area. The oxidative phosphorylation system is depicted in Figure 1, with a summary of the major nuclear gene mutations and clinical phenotypes associated with isolated enzyme deficiencies.
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COMPLEX I: STRUCTURAL GENE DEFECTS ASSOCIATED WITH ENCEPHALOPATHY |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Complex I (NADH-ubiquinone oxidoreductase) is the largest and least well understood of all the respiratory chain complexes. It is composed of 43 subunits, seven of which are encoded in mtDNA (3). Complex I accepts electrons donated from NADH-linked substrates and, after a complicated series of redox reactions, donates them to ubiquinone. The complex can be dissociated into a soluble peripheral arm containing the flavoprotein (FP) and iron protein (IP) subunits, and a hydrophobic arm (HP) embedded in the inner mitochondrial membrane. The FP fraction contains the NADH binding site and Fe–S clusters. The IP fraction also contains several Fe–S clusters, a subunit that is regulated by phosphorylation and a ubiquinone-binding subunit. All of the mtDNA-encoded subunits and at least 24 of the nuclear-encoded subunits are found in the HP fraction. Deficiencies in complex I are the most common respiratory chain defects, and about half of the patients present with Leigh syndrome (LS) with or without cardiomyopathy (4–6). LS is an early-onset, fatal neurodegenerative disorder characterized pathologically by bilateral lesions in the brainstem, basal ganglia, thalamus and spinal cord, and characterized clinically by psychomotor retardation and brainstem or basal ganglia dysfunction. Less common presentations of complex I deficiency include hepatopathy and tubulopathy, cardiomyopathy and cataracts, and lactic acidemia.
A systematic evaluation of 20 patients with complex I deficiency for mutations in the cDNAs of 35 nuclear-encoded structural subunits has revealed mutations in five structural genes. A tandem 5 bp duplication, which destroys a consensus phosphorylation site thought to be important in cAMP control of enzyme activity, was identified in the NDUFS4 gene in a patient with encephalopathy (7). Two LS patients had truncating mutations in the same gene and, interestingly, were reported to have a mild complex III mutation in addition to the complex I deficiency (8). A truncating mutation in NDUFS4 was found in an LS patient for whom blue native gel electrophoresis was used to demonstrate a defect in the assembly of the complex in the absence of this subunit (9). Missense mutations in the NDUFS7 and NDUFS8 genes, encoding Fe–S protein subunits, were also found in LS patients (10,11) and a missense and nonsense mutation in NDUFV1, coding for a subunit containing the NADH binding site, were found in two patients presenting with leukodystrophy and myoclonic epilepsy (12). Missense mutations in the NDUFS2 gene have been reported in three pedigrees with hypertrophic cardiomyopathy and encephalomyopathy (13). A survey of the cDNAs encoding the six most evolutionarily conserved structural subunits of complex I uncovered missense, nonsense and deletion mutations in the NDUFV1 and NDUFS1 genes in 6/36 patients with complex I deficiency (14). Interestingly, skin fibroblasts failed to demonstrate enzymatic deficiency in some cases, an observation that remains unexplained.
The genetic basis for the complex I deficiency could not be found in >50% of the patients examined by the Nijmegen group (15), suggesting that factors involved in the assembly or maintenance of the complex, which remain completely unknown in humans, are involved in the pathogenesis of these disorders.
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STRUCTURAL GENE DEFECTS IN COMPLEX II: LS AND A CANCER CONNECTION |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Complex II is the only respiratory chain complex whose subunits are entirely encoded by nuclear genes. It is composed of two soluble proteins, the FP (SDHA) and IP (SDHB) subunits, which are anchored on the matrix side of the inner membrane by two membrane subunits [cybS (SDHC) and cybL (SDHD)]. The soluble proteins contain the succinate dehydrogenase activity; the membrane-associated subunits contain a cytochrome b and the ubiquinone binding sites, and are responsible for transferring electrons into the ubiquinone pool from FADH-linked substrates. Missense mutations in the SDHA gene have been found in two families with autosomal recessive LS (16,17) and in a family with a late-onset neurodegenerative disease characterized by optic atrophy, ataxia and myopathy (18). In the latter family the mutation was found in only one allele and was associated with a 50% decrease in succinate dehydrogenase activity. This raises the interesting possibility that late-onset neurodegenerative disorders due to partial respiratory chain deficiency might be inherited as dominant traits.
Mutations in both SDHC and SDHD, encoding the large and small cytochrome b subunits, have been reported in families with autosomal dominant hereditary paraganglioma (PGL), a disorder characterized by the presence of benign, highly vascularized tumors of parasympathetic ganglia in the head and neck, most commonly occurring in the carotid body (19,20). About half of the PGLs are familial and these have been linked to three different loci (PGL1 to 11q23, PGL2 to 11q13 and PGL3 to 1q21). PGL1 is caused by missense or nonsense mutations in SDHD, shows incomplete penetrance and is only transmitted paternally (19). Although this suggested maternal imprinting, biallelic expression of the gene was observed in several tissues, and the maternal allele was invariably lost in all tumors (11/11) investigated. Thus, loss of heterozygosity appears necessary for tumor formation, although why it has always thus far involved the maternal allele remains unexplained. A mutation in the initiator codon of SDHC was found in a large PGL3 German pedigree (20). Loss of heterozygosity was also observed in the tumors from affected family members, but there were no parent-of-origin effects. The pathology of PGLs resembles that seen in the carotid body under conditions of chronic hypoxia suggesting that complex II plays a role as a cellular oxygen sensor (19).
Nonsense and missense germline mutations in SDHB and SDHD have been reported in patients with familial pheochromocytoma, with or without PGL, and in sporadic pheochromocytoma (21–23). Pheochromocytomas are chromaffin cell tumors that usually arise in the adrenal medulla, and more rarely in sympathetic ganglia. About 10% of these tumors are hereditary and they have been associated with different cancer syndromes including von Hippel–Lindau syndrome (VHL), multiple-endocrine neoplasia type 2 (MEN2) and more rarely neurofibromatosis (Nf1) (23). The association with VHL is interesting in the current context because the product of the VHL gene has been implicated, as a component of a ubiquitin ligase complex, in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that plays a key role in the cellular response to hypoxia (24). The regulatory HIF-
subunits are rapidly degraded under normoxic conditions, but are stabilized in hypoxic conditions, and in VHL-defective cells. The latter leads to an inappropriate expression of genes that contain a hypoxia response element such as vascular endothelial growth factor (VEGF), an angiogenic growth factor, and to highly angiogenic tumors (24). It is not clear, however, how this function of VHL relates to susceptibility to pheochromocytoma, as recent studies have demonstrated apparently normal HIF- ubiquitylation in Type 2C VHL patients, who only express susceptibility to pheochromocytomas (25,26).
The above studies clearly implicate three of the genes encoding structural subunits of complex II as tumor suppressors, and suggest a role in oxygen sensing and the hypoxia response (19,23), but the molecular basis for these effects remains to be determined. It is also not clear why mutations in SDHA should produce LS while mutations in the other three subunits are cancer susceptibility genes, with no evidence of central nervous system disorder.
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COMPLEX III: MUTATIONS IN AN ASSEMBLY FACTOR ASSOCIATED WITH A MULTISYSTEM DISORDER |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Complex III is composed of 11 polypeptide subunits, all but cytochrome b being encoded by nuclear genes. It catalyzes the transfer of electrons from ubiquinone to cytochrome c. While a number of mutations have been reported in cytb in patients with myopathy, with or without myoglobinuria (27), no mutations have yet been reported in the nuclear-encoded structural subunits. Missense mutations in BCS1L, a gene whose product is involved in the assembly of the complex have been found in four Turkish families with early-onset tubulopathy, hepatopathy and encephalopathy (28). BCS1L codes for an inner member protein of the AAA ATPase family and acts as a chaperone for the Rieske Fe–S subunit of complex III. Marked tissue-specific effects in the extent of the biochemical defect were reported and there was no evidence of an assembly defect in cultured skin fibroblasts (28).
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COMPLEX IV: MUTATIONS IN ASSEMBLY FACTORS ARE ASSOCIATED WITH SPECIFIC CLINICAL PHENOTYPES |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Complex IV (COX), the terminal enzyme in the mitochondrial respiratory chain, catalyzes the reduction of molecular oxygen by reduced cytochrome c. It is composed of 13 subunits, 10 of which are encoded by nuclear genes. Two of the nuclear subunits (VIa and VIIa) have tissue-specific isoforms. The three mtDNA-encoded subunits (COI–III) form the catalytic core of the enzyme and are similar to those from prokaryotes in which a fully functional enzyme complex generally requires only four subunits. Patients with autosomal recessive COX deficiency can present with a number of different clinical phenotypes including classical LS, a French–Canadian form of LS, fatal infantile COX deficiency, hypertrophic cardiomyopathy and myopathy, and a reversible COX deficiency confined to skeletal muscle (29). Mutations have not been identified in any of the 10 nuclear-encoded structural genes in patients with any of the above phenotypes (30,31). Several gene defects have, however, been reported in factors important in the biogenesis of the COX complex. Their identification has been greatly aided by studies of yeast pet mutants defective for COX assembly (32).
The first nuclear COX gene defect was discovered in classical LS. COX activity in these patients is reduced to 10–25% of control levels with no obvious tissue specificity in the severity of the deficiency. The gene defect in LS-COX patients was mapped to chromosome 9 by microcell-mediated chromosome transfer, and further localized to 9q34 by deletion mapping (33). Sequencing of SURF1, a candidate gene in this region because of its homology to SHY1, a yeast pet gene (34), showed loss-of-function (truncating) mutations in all patients (33,35). Mutations that result in premature stop codons have now been described in all nine exons of the SURF1 gene (36). A complex insertion/deletion mutation in exon 4 is a common allele in several populations and likely represents an ancient mutation. Missense alleles are uncommon and thus far have only been reported in combination with either splice site, frame shift or nonsense alleles. Immunoblot analyses of mitochondria isolated from fibroblasts of SURF1 patients show no detectable SURF1 protein, even in patients with missense mutations (37–39).
Mutations in SURF1 appear to be rather specific for LS as there are only two reported cases in non-LS patients with COX deficiency, both of whom had novel mutations (39,40). It is possible that some SURF1 protein accumulates in the CNS in these cases, accounting for the lack of typical neuropathology. It is not yet clear what proportion of LS-COX patients are accounted for by SURF1 mutations; in one series, 75% of patients had SURF1 mutations (41), in another only 26% (42).
SURF1 is not absolutely required for the assembly of COX, as the residual activity of COX in fibroblasts from SURF1 patients is similar to the relative amount of immunodetectable protein in the COX subunits (37,38), and the protein appears to be catalytically normal. SURF1 is an inner mitochondrial membrane protein with two predicted transmembrane spanning domains. Mutational analysis has demonstrated that the intact protein, except for a small C-terminal tail, is essential for function (37). Patients with SURF1 mutations show accumulation of an early assembly intermediate of the COX complex (38).
A French–Canadian form of COX-deficient LS is biochemically distinct from the classical disorder in that there is marked tissue specificity in the severity of the enzyme deficiency. Liver and brain are severely affected, whereas kidney and heart have almost normal activities. The gene for this syndrome maps to chromosome 2p16, in a region where no known structural or assembly COX gene is known (43).
Mutations in the human SCO2 gene, a mitochondrial copper chaperone, have been found to cause fatal, early-onset hypertrophic cardiomyopathy with encephalopathy (44,45). The severity of the COX deficiency is tissue-specific: cardiac and skeletal muscle are more affected than liver or fibroblasts. Most reported cases are compound heterozygotes for a common allele that produces an E140K substitution near the putative CxxxC copper binding site in the protein. The reason for this is unknown and studies of the homologous mutation in yeast Sco1 demonstrate that this allele does not have a respiratory deficiency in yeast (46). Consistent with this, the recent discovery that two patients homozygous for this mutation had a comparatively mild phenotype (47) demonstrate that this mutation is pathological in humans, but it is not as severe as the missense and nonsense alleles described in very early-onset cases. A minority of patients with early-onset hypertrophic cardiomyopathy (
20%) have mutations identified in SCO2 (45). Sequencing of the cDNAs for COX17 and SCO1, coding for two other proteins implicated in mitochondrial copper delivery, has not revealed any pathogenic mutations in these patients (48).
Mutations in SCO1 have recently been reported in a family with hepatopathy and ketoacidotic coma, but no cardiac symptoms (49). While the relative roles of SCO1 and SCO2 are still unclear, these data suggest that there may be tissue-specific features of mitochondrial copper delivery in humans. Analysis of 18 patients with a similar hepatic encephalopathy phenotype failed to reveal mutations in SCO1, SCO2 or in COX10 (49). A homozygous missense mutation in COX10, encoding the heme A farnesyltransferase, was reported in a patient presenting with leukodystrophy and proximal tubulopathy (50). Sequencing of COX10 in other patients with a similar clinical phenotype, or the same pattern on an immunoblot of COX subunits, failed to identify further positive pedigrees, underscoring the genetic heterogeneity in these cases (50).
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COMPLEX V: A PUTATIVE ASSEMBLY DEFECT ASSOCIATED WITH CARDIAC AND HEPATIC DYSFUNCTION |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Complex V, the ATP synthase, is composed of 16 subunits. Subunits a and A6L are encoded in mtDNA by the ATP 6 and 8 genes, respectively, and the rest are encoded in the nucleus. The complex consists of the membrane-spanning F0 segment, responsible for proton translocation, and the F1 stalk which extends into the matrix and contains the catalytic center. Mutations in ATP6 have been described in a syndrome of neuropathy, ataxia and retinitis pigmentosa (NARP) (51) and LS (52), but no mutations have yet been described in nuclear-encoded subunits. A patient with cardiomegaly, hepatomegaly and lactic acidosis has been described with a clear assembly defect, but the gene defect remains unknown (53).
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MULTIPLE RESPIRATORY CHAIN DEFECTS |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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Deficiencies that involve more than one respiratory chain complex are common in mtDNA mutations, the majority of which are due to tRNA mutations or deletions producing mitochondrial translation defects. They have also been reported in pediatric cases, and although no molecular defects are known in these instances, a locus for one such disorder in two families with fatal mitochondrial disease due to biochemical deficiencies in pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, NADH succinate cytochrome c reductase, and succinate dehydrogenase has been mapped to chromosome 2p14–13 by chromosome transfer (54).
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MAINTENANCE OF mtDNA INTEGRITY: AUTOSOMAL DOMINANT AND RECESSIVE PHENOTYPES PRODUCING MULTIPLE mtDNA DELETIONS |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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These disorders have been referred to as nuclear–mitochondrial communication disorders, and their molecular biological consequence is a loss of integrity of the mitochondrial genome, resulting in the accumulation of multiple mtDNA deletions. The most common such syndrome, progressive external ophthalmoplegia (PEO), is transmitted in most cases as an autosomal dominant trait (adPEO) (55), or more rarely as an autosomal recessive trait (arPEO) (56). The disease is characterized clinically by ophthalmoparesis and exercise intolerance with onset usually between 18 and 40 years of age (57). Linkage analysis detected pathogenic loci on chromosome 10q24 (58), 4q34–35 (59) and 15q22–q26 (60). There is at least one (and probably more) unidentified locus. The gene defect at the chromosome 4 locus was identified in the adenine nucleotide translocase 1 gene (ANT1) (61), which codes for a muscle-specific form of the protein. Missense mutations and a small duplication were identified in C10orf2, a putative helicase gene related to the phage T7 gene 4 primase/helicase, in two large families that showed linkage to chromosome 10, and in several families without linkage data (62). This protein is active as a hexamer in phage, and interestingly all of the human mutations clustered in the region of subunit association, although no defect in assembling the hexamer could be identified. The protein product of the gene has been called Twinkle, because it appears to associate with mitochondrial nucleoids, producing a star-like pattern in a night sky by immunocytochemistry. The gene is ubiquitously expressed, with highest expression in skeletal muscle. A missense mutation in a conserved polymerase domain of the mitochondrial
DNA polymerase POLG was reported in an adPEO family with multiple deletions linked to chromosome 15q22–q26 (60). Additional missense POLG mutations, outside of both the polymerase and exonuclease domains, were uncovered in two other families with apparently arPEO in the same study. Myoneurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disorder characterized by PEO, dementia with a progressive leukodystrophy, mitochondrial myopathy, peripheral neuropathy and prominent involvement of the gastrointestinal tract. This syndrome was linked to chromosome 22q13 (63) and shown to be caused by loss-of-function mutations in the thymidine phosphorylase gene (64). Thymidine phosphorylase converts thymidine to 2-deoxy D-ribose 1-phosphate and may function to regulate thymidine availability for DNA synthesis. Thymidine phosphorylase is widely expressed in human tissues, but paradoxically not in skeletal muscle, in which multiple mtDNA deletions are present in some but not all patients (64).
The disease mechanism in the multiple mtDNA deletion syndromes remains unknown, although it has been speculated that it could involve an imbalance of intramitochondrial nucleotide pools in the case of ANT1 and TP genes (61). One of the mutant Twinkle proteins was shown to have enhanced dNTPase activity, and it is possible that this rather than any helicase function is the basis for the molecular pathology (62). An imbalance in the intramitochondrial pools could induce stalling of the DNA polymerase, perhaps linking these three gene defects with those reported in the polymerase itself.
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INDIRECT EFFECTS ON OXIDATIVE PHOSPHORYLATION |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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A number of Mendelian disorders have been identified by linkage analysis that can be considered as mitochondrial diseases, although the effects of these mutations on oxidative phosphorylation per se have not generally been established. The clearest example in which the respiratory chain is affected is Freidreich’s ataxia, which is caused by the expansion of intronic repeats in the frataxin gene (reviewed in 65). Although the exact function of frataxin remains controversial, it plays a role in some aspect of mitochondrial iron handling, and a deficiency in the protein leads to marked reductions in the activities of mitochondrial enzymes with Fe–S centers, notably complex I and III and aconitase (66). Mohr–Tranebjerg syndrome is an X-linked recessive disorder associated with hearing loss, dystonia, dementia and optic atrophy that is caused by mutations in the DPP gene, coding for Tim8, a protein involved in one of the mitochondrial import machineries (67). An autosomal dominant form of hereditary spastic paraplegia linked to the chromosome is caused by mutations in the paraplegin gene, a member of the AAA ATPase family, related to proteins whose function in yeast is related to turnover of mitochondrial inner membrane proteins (68). Finally, a dominantly inherited form of optic atrophy has been reported due to the OPA1 gene whose protein product belongs to the dynamin family and may be involved in the control of mitochondrial morphology (69,70).
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CONCLUSIONS AND FUTURE PROSPECTS |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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The last few years of investigation into the nuclear basis for oxidative phosphorylation disorders have been nearly as productive as the first few years of mtDNA mutation detection, following the initial reports of mutations in that genome in 1988. While genes coding for structural components of the respiratory chain complexes have been identified, those encoding factors involved in the assembly or maintenance of the respiratory chain complexes appear to be at least as important as causes of these disorders. Most of the nuclear genes associated with early-onset autosomal recessive oxidative phosphorylation diseases are ubiquitously expressed housekeeping genes, yet tissue specificity in the extent of the biochemical deficiency is common, and the clinical phenotypes diverse. The prominent involvement of the nervous, cardiac and skeletal muscle systems supports the contention that tissues with high aerobic energy demands will be most affected in oxidative phosphorylation disorders, but this simple view cannot explain the selective vulnerability of different organs when, for instance, different assembly factors for COX are mutated. It also cannot explain the selective involvement of different subpopulations of cells in the central nervous system, characteristic of Leigh or Leigh-like pathology, the most common presentation of oxidative phosphorylation disease in infants. There are hints of a common molecular mechanism in the nuclear–mitochondrial communication disorders, perhaps involving stalling of the
DNA polymerase due to imbalance in the nucleotide pools or to defects in the enzyme itself. The connection between mutations in the structural components of complex II and cancer is unexpected, and promises to open up yet another area of investigation of mitochondrial function, their role in oxygen sensing and the hypoxia response. The molecular basis for the majority of autosomal recessive oxidative phosphorylation defects in the pediatric population remains unknown. In addition, almost nothing is known about the extent of genetic heterogeneity in this patient group; thus far, only a single large genetic complementation group has been identified (SURF1), and there is no indication that anything similar will be uncovered in the other patients. Thus, hunting for the defective genes in the remaining cases will involve some sort of functional complementation approach such as microcell-mediated chromosome transfer, or direct cloning by complementation with retroviral cDNA expression libraries. With the near completion of the human genome project, it is likely that we will have a good catalogue of the nuclear gene defects associated with oxidative phosphorylation disorders in the next few years.
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ACKNOWLEDGEMENTS |
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Research in this author’s laboratory is supported by grants from the Canadian Institutes for Health Research, the March of Dimes Birth Defects Foundation and the Muscular Dystrophy Association (USA and Canada). E.A.S. is an MNI Killam Scholar.
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FOOTNOTES |
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+ Tel: +1 514 398 1997; Fax: +1 514 398 1509; Email: eric@ericpc.mni.mcgill.ca
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCOMPLEX I: STRUCTURAL GENE...STRUCTURAL GENE DEFECTS IN...COMPLEX III: MUTATIONS IN...COMPLEX IV: MUTATIONS IN...COMPLEX V: A PUTATIVE...MULTIPLE RESPIRATORY CHAIN...MAINTENANCE OF mtDNA INTEGRITY:...INDIRECT EFFECTS ON OXIDATIVE...CONCLUSIONS AND FUTURE PROSPECTSREFERENCES |
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