Mitochondrial DNA Medicine

Transcription

1 DOI /s ORIGINAL PAPER Mitochondrial DNA Medicine Salvatore DiMauro Ó The Biochemical Society 2007 Abstract The small, maternally inherited mitochondrial DNA (mtdna) has turned out to be a hotbed of pathogenic mutations: 15 years into the era of mitochondrial medicine, over 150 pathogenic point mutations and countless rearrangements have been associated with a variety of multisystemic or tissue-specific human diseases. MtDNA-related disorders can be divided into two major groups: those due to mutations in genes affecting mitochondrial protein synthesis in toto and those due to mutations in specific protein-coding genes. Here we review the mitochondrial genetics and the clinical features of the mtdna-related diseases. Keywords mtdna Epidemiology Mitochondrial diseases Mitochondrial DNA (mtdna) is the result of endosymbiosis, which occurred about 1.5 billion years ago, when protobacteria populated primordial eukaryotic cells and took permanent residence in the new environment. MtDNA, a relic but not a fossil, has lost much of its independence and keeps functioning under the overarching control of the nuclear genome. Mitochondria are ubiquitous in eukaryotes and are essential for survival. Their primary function is to support aerobic respiration and to provide energy and heat. Mitochondria also play other important roles, including cell signalling for apoptotic cell death. Mitochondria contain two membranes, an outer membrane (OMM) and an inner membrane (IMM) that invaginates to form cristae. Although traditionally considered (and usually represented) as small individual organelles, in fact mitochondria form complex branching networks by virtue of their ability to move, fuse, and split. The S. DiMauro (&) Department of Neurology, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA sd12@columbia.edu

2 abundance of mitochondria varies from tissue to tissue, and is related to that tissue s dependence upon oxidative phosphorylation for energy provision. Thus, neurones, and cardiac and skeletal muscle have a high density of mitochondria, which, to some extent, explains their vulnerability to energy-dependent defects resulting from mitochondrial abnormalities. Human mtdna (Fig. 1) is a 16,569-kb circular, double-stranded molecule, which contains 37 genes: 2 rrna genes, 22 trna genes, and 13 structural genes encoding subunits of the mitochondrial respiratory chain, which is the business end of oxidative metabolism, where ATP is generated (DiMauro and Schon 2003). Reducing equivalents produced in the Krebs cycle and in the ß-oxidation spirals are passed along a series of protein complexes (the electron transport chain) embedded in the IMM and consisting of four multimeric complexes (I IV) plus two small electron carriers, coenzyme Q (or ubiquinone) and cytochrome c (Fig. 2). The energy generated by the reactions of the electron transport chain is used to pump protons from the mitochondrial matrix into the space between the IMM and OMM. This creates an electrochemical proton gradient, which is utilized by complex V (or ATP synthase), a tiny rotary machine that generates ATP as protons flow back into the matrix through its membrane-embedded F0 portion, the rotor of the turbine (DiMauro and Schon 2003). Fig. 1 Morbidity map of the human mitochondrial genome. The map of the 16,569 bp mtdna shows differently colored areas representing the protein-coding genes for the seven subunits of complex I (ND), the three subunits of cytochrome c oxidase (CO), cytochrome b (cyt b), and the two subunits of ATP synthase (A6 and A8), the 12S and 16S rrnas (12S, 16S), and the 22 trnas identified by one-letter codes for the corresponding amino acids. See list of abbreviations. FBSN = familial bilateral striatal necrosis

3 Fig. 2 Schematic view of the mitochondrial respiratory chain, showing nuclear DNA-encoded (blue) and mtdna-encoded (red) subunits. Protons (H+) are first pumped from the matrix to the intermembrane space through complexes I, III, and IV, then flow back into the matrix through complex V to produce ATP. Coenzyme Q (CoQ) and cytochrome c (Cyt c) are electron carriers The physical characteristics and mode of inheritance of mtdna define some rules of mitochondrial genetics, which are distinct from those of mendelian genetics. The most important features of mitochondrial genetics are: Heteroplasmy and Threshold Effect Each cell contains 100s or 1,000s of mtdna copies. During cell division, mtdna molecules distribute randomly among daughter cells. In normal tissues, all copies of mtdna molecules are identical (homoplasmy). Pathogenic mutations of mtdna usually affect some but not all mtdnas within a cell, a tissue, or an individual, which results in the admixture of mutant and wild-type mtdnas (heteroplasmy), and the clinical phenotype of a particular mutation of mtdna mutation is mainly determined by the relative proportion of wild-type and mutant genomes in different tissues. Depending on the energetic demands of a particular cell, the level of mutated genomes required to produce a phenotypic expression (and, ultimately, a disease) varies (threshold effect). Although thresholds differ in different tissues, when they are surpassed, ATP production falls below energy demands. Mitotic Segregation At cell division, the proportion of mutant mtdnas in daughter cells may shift and the phenotype may change accordingly. This phenomenon, called mitotic segregation, explains how certain patients with mtdna-related disorders may actually shift from one clinical phenotype to another as they grow older. Maternal Inheritance At fertilization, all mtdna derives from the oocyte. As a consequence, the pattern of transmission of mtdna (and, of course, of mtdna point mutations) is radically different from mendelian inheritance. A mother carrying a mtdna point mutation will pass it on to all her children (males as well as females), but only her daughters will transmit it to their progeny. A disease expressed in both sexes but without evidence of paternal transmission is strongly suggestive of a mtdna point mutation. Surprisingly, one case of paternally-inherited mtdna has been reported in skeletal muscle from a patient with a myopathy due to a microdeletion in the ND2 gene (Schwartz and Vissing 2002). However, further studies of mitochondrial haplotypes in other patients with similar mitochondrial myopathies and their relatives have shown that such mode of inheritance is the proverbial exception that confirms the rule (Filosto et al. 2003; Taylor et al. 2003). Until relatively recently, mitochondrial disorders were considered rare diseases of purely academic interest. Only a few centers throughout the world had clinical and laboratory expertise in mitochondrial medicine, and a general lack of awareness of mitochondrial disease by practitioners left many patients undiagnosed. However, in the past 15 years there has been a surge of interest in human mitochondrial diseases.

4 A flurry of epidemiological studies in recent years has confirmed the notion that mitochondrial diseases are, in fact, among the most common genetic disorders and a major burden for society. A population-based study of a single pathogenic mtdna mutation, carried out in Finland (Majamaa et al. 1998) estimated minimum point prevalence of the 3243A>G mutation in the general population to be 16.3/100,000. Another population-based study of all mitochondrial disorders in northeast England (Chinnery et al. 2000) was based upon adults with suspected mitochondrial disease referred to a single center in Newcastle upon Tyne, which serves a population of 2122,290. Thorough clinical, biochemical and genetic studies of patients referred over a 15-year period gave a minimum point-prevalence of 6.57/100,000. Further, it was estimated that 12.48/100,000 or 1 in 8013 individuals within the region either had mitochondrial disease or were at risk of developing mitochondrial disease. A more detailed clinical and genetic study of Leber hereditary optic neuropathy (LHON) refined the prevalence for this disorder to 11.82/100,000 (Man et al. 2003), and confirmed the predominance of the 11778G>A ND4 mutation as a cause of LHON (56%), followed by the 3460G>A ND4 mutation (31%), and the 14484T>C ND6 mutation (6.3%). This work established LHON as a major cause of visual loss in young adults, affecting one in 14,067 males (Man et al. 2003). Two studies of mitochondrial disease in children were conducted, one in Sweden, the other in Australia. The Swedish study, based upon a population of 358,616 patients studied over a 15-year period (Darin et al. 2001) identified 32 affected children under 16 years of age giving a minimum point prevalence of 4.7/100,000 or 1 in 21,277. In preschool children, the incidence of mitochondrial encephalomyopathies was 8.9/ 100,000 (Darin et al. 2001). The Australian study was based upon referrals to the Melbourne Children s hospital over a 10-year period (Skladal et al. 2003) and determined the minimum birth prevalence of childhood respiratory chain diseases as 5.0/100,000 or one in 20,000 (Skladal et al. 2003). When one combines the results of the epidemiological data on childhood and adult mitochondrial disease, the minimum prevalence is at least one in 5,000, and could be much higher. By convention, the term mitochondrial diseases refers to disorders of the mitochondrial respiratory chain, thus excluding dysfunction in other metabolic pathways located in the mitochondria, i.e. pyruvate metabolism, Krebs cycle, fatty acid oxidation. The respiratory chain is the only metabolic pathway in the cell that is under the dual control of the mtdna and the nuclear genome (ndna). Therefore, a genetic classification of the mitochondrial diseases distinguishes disorders due to mutations in mtdna, which are governed by the relatively lax rules of mitochondrial genetics, and disorders due to mutations in ndna, which are governed by the stricter rules of mendelian genetics. Mutations in mtdna can be further divided into those that impair mitochondrial protein synthesis in toto and those that affect any one of the 13 respiratory chain subunits encoded by mtdna. Disorders due to mutations in ndna are more abundant not only because most respiratory chain subunits are nucleus-encoded but also because correct assembly and functioning of the respiratory chain require numerous steps, all of which are under the control of ndna. These steps (and related diseases) include: (i) synthesis of assembly of respiratory chain proteins; (ii) intergenomic signaling; (iii) mitochondrial importation of ndna-encoded proteins; (iv) control of mtdna translation; (v) synthesis of inner mitochondrial membrane phospholipids; (vi) mitochondrial motility and fission. Recently, primary coenzyme Q10 (CoQ 10 ) deficiency has been included among the mitochondrial respiratory chain disorders because of its central role as an electrons

5 carrier from complex I and II to complex III. CoQ10 deficiency is an autosomal recessive condition with a clinical spectrum that encompasses at least five major phenotypes: (1) encephalomyopathy characterized by the triad of recurrent myoglobinuria, brain involvement and ragged red fibers; (2) severe infantile multisystemic disease; (3) cerebellar ataxia; (4) Leigh syndrome with growth retardation, ataxia and deafness; and (5) isolated myopathy (Quinzii et al. 2007). Essential clinical features for each group of mitochondrial diseases are reviewed in the rest of this issue of the Bioscience Reports. References Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM (2000) Epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48: Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M (2001) The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 49: DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348: Filosto M, Mancuso M, Vives-Bauza C, Vila MR, Shanske S, Hirano M, Andreu AL, DiMauro S (2003) Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann Neurol 54: Majamaa K, Moilanen JS, Uimonen S, Remes AM, Salmela PI, Karppa M, Majamaa-Volti KAM, Rusanen H, Sorri M, Peuhkurinen KJ, Hassinen IE (1998) Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 63: Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (2003) The epidemiology of leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72: Quinzii CM, DiMauro S, Hirano M (2007) Human coenzyme Q10 deficiency. Neurochem Res 32: Schwartz M, Vissing J (2002) Paternal inheritance of mitochondrial DNA N Engl J Med 347: Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126: Taylor RW, McDonnell MT, Blakely EL et al (2003) Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann Neurol 54: