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Cshperspect-MIT-A021220 1..47 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease Douglas C. Wallace and Dimitra Chalkia Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Correspondence: [email protected] The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common “complex” diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these “heteroplasmic” mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical vari- ability of a range of diseases. Maternal inheritance and heteroplasmy also pose major chal- lengers for the diagnosis and prevention of mtDNA disease. THE GENETIC CHALLENGES OF mtDNA most important bioenergetic genes. So mtDNA DISEASES defects impinge on a wide spectrum of cellular functions. t is has become increasingly clear that mito- A large number of pathogenic mtDNA mu- Ichondrial dysfunction lies at the nexus of a tations have been identified and the more severe wide range of metabolic and degenerative dis- mutations are frequently mixed with normal eases, cancer, and aging. Two major reasons for mtDNAs within the cell, a state known as het- why mitochondrial dysfunction has been over- eroplasmy. Heteroplasmic alleles can shift in looked in “complex” diseases is that subtle bio- percentage during both mitotic and meiotic energetic alterations can have major clinical cell division, leading to a potentially continuous consequences and mitochondrial defects can array of bioenergetic defects, a process known be generated by the unique quantitative genetics as replicative segregation. As the percentage of of the maternally inherited mitochondrial DNA mutant mtDNAs increases, the resulting bio- (mtDNA). energetic defect becomes increasingly severe. The mitochondrial genome encompasses Because different tissues have different bioener- between 1000 to 2000 nuclear DNA (nDNA) getic thresholds, as a patient’s bioenergetic ca- genes plus thousands of copies of the maternally pacity declines it eventually falls below the min- inherited mtDNA. The mtDNA codes for the imum threshold for that tissue and symptoms Editors: Douglas C. Wallace and Richard J. Youle Additional Perspectives on Mitochondria available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021220 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a021220 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press D.C. Wallace and D. Chalkia ensue. Because the tissues and organs with the tions have estimated that the incidence of clini- highest bioenergetic requirements are also those cal mitochondrial diseases is about one in 5000 that are primarily affected in the common met- (Schaefer et al. 2004, 2008). More surprising, abolic and degenerative diseases, it follows that a survey of newborn cord bloods revealed that mitochondrial dysfunction may be a major con- one in 200 infants harbored one of 10 common tributor to complex diseases. pathogenic mtDNA mutations (Elliott et al. Women that harbor deleterious heteroplas- 2008; Chinnery et al. 2012). Hence, pathogenic mic mutations have a high probability of hav- mtDNA mutations are very common and con- ing affected children, the nature and severity stantly arising. of the phenotype depending on the mtDNA mutation and the percentage of heteroplasmy. Human OXPHOS and the Range Cells and individuals can accumulate an array of Phenotypes: Conception to Old Age of different mtDNA mutations over time, the aggregate of which degrade the energetic ca- To understand the clinical implications of pacity of the cell. Such mutations are important mtDNA mutations, it is essential to understand in aging and cancer. Given the enormous po- the central role that mitochondrial oxidative tential explanatory power of heteroplasmic phosphorylation (OXPHOS) plays in cellular mtDNA mutations, it is striking that very little biology. The mitochondria oxidize the calories is known about the origin, genetics, and phe- in our diet with the oxygen that we breathe to notypic effects of heteroplasmic mtDNA mu- generate 90% of cellular energy. In OXPHOS, tations. electrons (reducing equivalents) derived from our food flow down the mitochondrial in- ner membrane electron transport chain (ETC) HUMAN mtDNA GENETICS from reduced to oxidized states, ultimately That mtDNA mutations could cause disease terminating with reduction of oxygen to water. was first reported at the molecular level in The ETC is initiated with oxidation of NADH 1988 with the demonstration that isolated pa- by complex I (NADH:CoQ oxidoreductase or tients with mitochondrial myopathy could har- NADH dehydrogenase) or succinate by com- bor heteroplasmic mtDNA deletions (Holt et al. plex II (succinate:CoQ oxidoreductase or succi- 1988); that the maternally inherited sudden on- nate dehydrogenase). The electrons are then set blindness disease, Leber hereditary optic transferred to coenzyme Q (CoQ), complex neuropathy (LHON), was caused by a homo- III, cytochrome c, complex IV (cytochrome c plasmic missense mutation in the ND4 gene at oxidase or COX), and finally to oxygen. As the nt 11778G.A (arginine codon 340 to histidine, electrons traverse complexes I, III, and IV, the R340H) (Wallace et al. 1988a); and that myo- energy released is used to pump protons from clonic epilepsy and ragged red fiber disease the mitochondrial matrix across the mito- (MERRF) was caused by a heteroplasmic muta- chondrial inner membrane to the intermem- tion in the tRNALys gene at nt 8344A.G (Wal- brane space (Wallace 2005, 2007, 2011). This lace et al. 1988b; Shoffner et al. 1990). These creates a transmembrane electrochemical gradi- discoveries set the stage for investigating and ent of 0.2 volts. This potential energy can then understanding a broad range of enigmatic fami- be used to drive OXPHOS complex V (Hþ- lial and age-related diseases. translocating ATP synthase) to condense ADP and phosphate (Pi) to generate ATP (Mitchell 1961), thus coupling oxidation by the ETC Incidence of mtDNA Mutations with phosphorylation by the ATP synthase. and Disease The mitochondrial ATP is then exported to Mutations in mtDNA are surprisingly common. the cytosol via the adenine nucleotide translo- Geneticepidemiological studies quantifying only cators (ANTs), where the ATPenergizes cellular the most common pathogenic mtDNA muta- reactions and drives work. 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a021220 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Mitochondrial DNA Genetics In addition to generating ATP energy, the mtDNA Mutations mitochondria regulate cytosolic Ca2þ levels, which in turn modulate cellular and mitochon- The mtDNA genes have a very high sequence drial metabolic pathways, control the cellular evolution rate, on the order of 10–20 times REDOX state that regulates a wide array of cel- that of comparable nDNA genes (Brown et al. lular enzymatic reactions and transcription fac- 1982; Neckelmann et al. 1987; Wallace et al. tors via thiol-disulfide interconversion, regulate 1987). This is the product of both an exception- mitochondrial ROS production that is both a ally high mutation rate, perhaps 100- to 1000- signal transduction agent that impinges on fold higher than nDNA genes, times an mtDNA molecules such as HIF and RAS, and is the ma- mutant fixation rate: E ¼ mF where E is the jor source of oxidative stress that can activate sequence evolution rate, m the mutation rate, the innate immunity response through NF-kB and F the fixation rate. When a new mutation signaling. When mitochondria experience ex- arises in the mtDNA, it creates an intracellular treme stress (elevated Ca2þ and ROS, depleted heteroplasmic mixture of mutant and normal adenine nucleotides, and reduced membrane mtDNAs, but the mutant mtDNA is but one potential), this can activate the mitochondrial among thousands of nonmutant mtDNAs. In permeability transition pore (mtPTP) thus ini- some manner, the initial mutant mtDNA be- tiating apoptosis and necrosis (Wallace 2005, comes enriched within certain cells, ultimately 2011, 2012, 2013a,b; Wallace et al. 2013). coming to predominate and influence the cel- lular and patient phenotype. The mechanism by Mitochondrial Genetics which this enrichment occurs in either germline or somatic cells remains a mystery. The mtDNA Once an mtDNA mutation reaches an ap- The mtDNA (Fig. 1) codes for the 13 most im- preciable level within cells, the percentage of portant OXPHOS polypeptides. These include mutant mtDNAs can drift by replicative segre- seven of the 45 polypeptides of OXPHOS gation. For an embryo generated by the fertili- complex I (ND1-3, ND4L, ND4-6): one of the zation of a heteroplasmic oocyte, the percentage 11 polypeptides of complex III (cytochrome b, of mutant and normal mtDNAs in different de- cytb), three of the 13 polypeptides of complex scendant tissues and
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