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Mitochondrial Dna Mutations in Human Disease REVIEWS MITOCHONDRIAL DNA MUTATIONS IN HUMAN DISEASE Robert W. Taylor and Doug M. Turnbull Abstract | The human mitochondrial genome is extremely small compared with the nuclear genome, and mitochondrial genetics presents unique clinical and experimental challenges. Despite the diminutive size of the mitochondrial genome, mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely. Until recently, mitochondrial genetics and diseases that of developing it7,8. These estimates do not include the are due to defects in mitochondrial DNA (mtDNA) recent apparent association of mtDNA mutations and were often considered to be curiosities, outside main- common clinical features (for example, hypertension)9, stream genetics. These views were not helped by the which indicate that the incidence could be higher still. different genetic rules by which mtDNA is inherited In addition, there is increasing evidence from animal compared with nuclear DNA, the presence of sev- models10 and human studies11 that acquired mtDNA eral mtDNA copies in individual cells and a belief mutations and mitochondrial dysfunction are involved that mtDNA disease is rare. In addition, the clinical in ageing and age-related diseases such as diabetes12,13. syndromes caused by mtDNA mutations have vari- Although our present knowledge already indicates that able phenotypes and are often described by instantly mtDNA mutations are an important cause of disease, forgettable eponyms or acronyms1. These views per- the true impact of these mutations on human health haps ignore the fact that the mitochondrial genome remains to be determined. is central to the study of evolutionary genetics, has This review focuses on abnormalities of the mito- an important role in forensic medicine2 and that the chondrial genome in relation to human disease. human, bovine and mouse mitochondrial genomes Mitochondrial disease can also arise from nuclear were the first mammalian genomes to be completely gene disorders because most proteins involved in sequenced3–5. mitochondrial metabolism and all those involved in The increasing ease with which the mitochondrial mtDNA maintenance are nuclear-encoded. Mutations genome can be analysed, and the availability of a con- in these nuclear genes can mimic the features seen in sensus human sequence6, have both helped to recog- patients with mtDNA defects, and indeed some nuclear Mitochondrial Research nize mtDNA disorders as a frequent cause of genetic genetic disorders result in secondary abnormalities of Group, School of Neurology, disease. It is difficult to estimate the true prevalence the mitochondrial genome. Excellent reviews describe Neurobiology and Psychiatry, The Medical of mtDNA disease owing to its many clinical guises, the defects that are due to mutations in nuclear genes School, University of presentations and the involvement of numerous that are involved in mitochondrial oxidative metabo- Newcastle upon Tyne, NE2 causative mutations. Data on a single-point mutation lism1,14,15. Here we review our current understanding 4HH, United Kingdom. (3243A>G) in Finland indicate that approximately 1 of the role of mtDNA in human disease and highlight Correspondence to D.M.T. e-mail: d.m.turnbull@ncl. in 6,000 individuals are affected, whereas estimates areas that are either controversial or merit further stud- ac.uk from the British population intimate that about 1 in ies. We first review the basic features of mitochondrial doi:10.1038/nrg1606 3,500 people either have mtDNA disease or are at risk genetics. Much progress has been made in this area NATURE REVIEWS | GENETICS VOLUME 6 | MAY 2005 | 389 © 2005 Nature Publishing Group REVIEWS ab12S rRNA F D-loop T CO2 ATP 16S V rRNA Cyt b OXPHOS Heavy strand complexes L P Mitochondrial Carbohydrate O TCA DNA ND1 H cycle E I ND6 M Q Mitochondrial DNA Acetyl-CoA ND5 ND2 A N Light Fatty acids β-oxidation W C Y L strand OXPHOS O S complexes L S H COI ND4 Mitochondrion ATP D R ND4L G K ND3 COII 8 6 COIII ATPase Figure 1 | The role of the mitochondrial genome in energy generation. a | This highlights the importance of the mitochondrial genome in contributing polypeptide subunits to the five enzyme complexes that comprise the oxidative phosphorylation (OXPHOS) system within the inner mitochondrial membrane — the site of ATP synthesis. The reoxidation of reducing equivalents (NADH (reduced nicotinamide adenine dinucleotide) and FADH2 (reduced flavin adenine dinucleotide)) that are produced by the oxidation of carbohydrates (the tricarboxylic acid (TCA) cycle) and fatty acids (β-oxidation) is coupled to the generation of an electrochemical gradient across the inner mitochondrial membrane, which is harnessed by the ATP synthase to drive the formation of ATP. b | A map of the human mitochondrial genome. The genes that encode the subunits of complex I (ND1–ND6 and ND4L) are shown in blue; cytochrome c oxidase (COI–COIII) is shown in red; cytochrome b of complex III is shown in green; and the subunits of the ATP synthase (ATPase 6 and 8) are shown in yellow. The two ribosomal RNAs (rRNAs; 12S and 16S, shown in purple) and 22 tRNAs, indicated by black lines and denoted by their single letter code, which are required for mitochondrial protein synthesis are also shown. The displacement loop (D-loop), or non-coding control region, contains sequences that are vital for the initiation of both mtDNA replication and transcription, including the proposed origin of heavy-strand replication (shown as OH). The origin of light-strand replication is shown as OL. and a clear understanding is important to further our tides of the OXPHOS system and the necessary RNA knowledge of the diagnosis, pathogenesis and treat- machinery (2 rRNAs and 22 tRNAs) for their transla- ment of mtDNA disease. We then turn to clinical syn- tion within the organelle (FIG. 1). The remaining protein dromes that are due to mtDNA mutations, recognizing subunits that make up the respiratory-chain complexes, that mtDNA mutations might cause various clinical together with those required for mtDNA maintenance, features, which often makes diagnosis a considerable are nuclear-encoded, synthesized on cytoplasmic ribos- challenge. Even when diagnosed, there is no cura- omes, and are specifically targeted and sorted to their tive treatment for patients who have mtDNA disease. correct location within the organelle. Nonetheless, there are several experimental possibili- Mitochondrial genetics is different from Mendelian ties to either prevent transmission or to correct the genetics in almost every aspect, from the uniparental genetic defect and these are discussed here. Although inheritance of disease mutations, to the presence of models of mtDNA disease exist, these are predomi- many copies of the genome within a single cell and the nantly cell-based rather than transgenic mouse mod- basic mechanisms that underlie replication and control els. Some valuable models are available, but few mimic of transcription TABLE 1. The differences between the the characteristics of pathogenic mtDNA mutations. two genetic systems that are in human cells are prob- We conclude by considering the possible role of the ably a relic of evolution16, but lead to some fascinating mitochondrial genome in ageing, which, despite much biology that dictates the functional consequences of speculation, has only recently been supported by firm mtDNA mutations. evidence from an animal model. Replication, transcription and translation of mito- Mitochondrial genetics: the basics chondrial DNA. Both replication and transcription are Mitochondria are found in all nucleated cells and are important in terms of understanding the development of the principal generators of cellular ATP by oxidative mtDNA mutations and their biochemical consequences. phosphorylation (OXPHOS), incorporating the elec- There is now good evidence to indicate that the minimal tron-transferring respiratory chain (complexes I–IV) mitochondrial replisome17 consists of several proteins. and the ATP synthase (complex V). Mitochondria are These include: the heterodimeric mtDNA polymerase the only location of extra-chromosomal DNA within γ, which consists of a catalytic subunit with proof-read- the cell (except in plant chloroplasts), and they are ing ability (PolgA) and a processivity subunit (PolgB)18, under the dual genetic control of both nuclear DNA and Twinkle, which has 5′–3′ DNA helicase activity19, and a the mitochondrial genome. The mitochondrial genome mitochondrial single-stranded binding protein. Together consists of a multicopy, circular dsDNA molecule (16.6 with mitochondrial transcription factor A (TFAM), kb in humans), which encodes 13 essential polypep- these proteins associate with mtDNA to form structures 390 | MAY 2005 | VOLUME 6 www.nature.com/reviews/genetics © 2005 Nature Publishing Group REVIEWS that are termed NUCLEOIDS, which are believed to be the processed to produce individual tRNA and mRNA units of mtDNA transmission and inheritance. molecules29,30. To initiate transcription, the dedicated The mode of mtDNA replication has recently mitochondrial RNA polymerase
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