The Genom of Homo sapiens.pdf

mtDNA Variation, Climatic Adaptation, DegenerativeDiseases, and LongevityD.C. WALLACE, E. RUIZ-PESINI, AND D. MISHMARCenter for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine,California 92697-3940The mtDNA encodes 13 polypeptides that are criticalfor mitochondrial energy metabolism. These include 7 ofthe approximately 46 polypeptides of respiratory complexI (ND1, 2, 3, 4L, 4, 5, 6), 1 of the 11 polypeptides ofcomplex III (cytb), 3 of the 13 polypeptides of complexIV (COI, II, III), and 2 of the 17 polypeptides of complexV (ATP6, 8). In addition, the mtDNA encodes the smalland large rRNAs and the 22 tRNAs required for mitochondrialprotein synthesis (Fig. 1).The mitochondrial energy-generating pathway, oxidativephosphorylation (OXPHOS), oxidizes the carbohydratesand fats of our diet with the oxygen that we breatheto generate energy in the form of ATP and heat to maintainour body temperatures. Electrons from dietary caloriespass sequentially through complex I, coenzyme Q(CoQ), complex III, cytochrome c, complex IV, and thenatomic oxygen (1/2 O 2 ) to produce water (H 2 O). The energythat is released from this electron transport chain(ETC) is used to pump protons across the mitochondrialinner membrane through complexes I, III, and IV to generatean electrochemical gradient, ∆P = ∆Ψ + ∆pH. Thepotential energy stored in ∆P is then used to generateATP by passage through the proton channel in the ATPsynthase (complex V). The efficiency with which complexesI, III, and IV pump protons out of the mitochondrialinner membrane and with which the passage of protonsback through complex V is converted into ATP iscalled the coupling efficiency. Highly coupled mitochondriaproduce the maximum amount of ATP and minimumheat, whereas loosely coupled mitochondria generate lessATP and more heat.As a toxic by-product of OXPHOS, the mitochondriagenerate most of the endogenous reactive oxygen species(ROS) of the cell (Kagawa et al. 1999; Wallace and Lott1999; Kadenbach 2003). The rate of ROS production istied to the degree to which complex I, coenzyme Q, andcomplex III are reduced and thus have excess electronsthat can be transferred directly to molecular oxygen (O 2 )–to generate superoxide anion (O 2),the first of the ROS.Superoxide anion is converted to H 2 O 2 by manganese superoxidedismutase (MnSOD), and H 2 O 2 is converted to•OH or H 2 O. The mitochondrial ROS can react with theDNA, proteins, and lipids of the mitochondrion and thenucleus-cytosol. Ultimately, the mitochondria becomesufficiently impaired that the cell malfunctions. Thisleads to the activation of the mitochondrial permeabilitytransition pore (mtPTP), which initiates apoptosis, killingthe cell and its defective mitochondria. When sufficientcells in a tissue are lost, organ dysfunction occurs, resultingin degenerative diseases and aging (Wallace 1999,2001b; Friberg and Wieloch 2002).The maternally inherited mtDNA has a very high mutationrate, perhaps because of the high oxidative damagethat it sustains. As a consequence, pathogenic mtDNAmutations are common (Jacobs 2003). Examples ofpathogenic mutations in mtDNA protein synthesis genesinclude a 12S rRNA mutation at nucleotide position (np)1555G associated with sensory neural hearing loss, atRNA Leu(UUR) mutation at np 3243G associated with cardiomyopathyand stroke-like episodes at high percentageof mutant mtDNAs (heteroplasmy), or adult-onset diabetesat a low percentage of heteroplasmy; a tRNA Glnmutation at np 4336C associated with late-onsetAlzheimer disease (AD) and Parkinson disease (PD); anda tRNA Lys mutation at np 8344G associated with epilepsyand progressive muscle weakness. Examples ofpathogenic protein missense mutations include severalcomplex I mutations (ND1 np 3460A, ND4L np 10663C,ND4 np 11778A, and ND6 np 14484C) that cause Leberhereditary optic neuropathy (LHON), an ND6 np 14459Amutation that causes generalized dystonia and LHON,and the ATP6 np 8993G mutation that can cause retinitispigmentosa, macular degeneration, mental retardation,and lethal childhood Leigh syndrome, depending on thepercentage heteroplasmy (Fig. 1) (Tatuch et al. 1992;Wallace 2001a).Since nucleotide substitutions occur at random, a widevariety of mutations accumulate over time. Most of thesewill be deleterious and eliminated by purifying selection,resulting in genetic diseases. Others could be neutral,such as the third codon position changes, and these couldaccumulate by chance through genetic drift. Occasionally,a mutation could be advantageous in a new environment,becoming established through adaptive selection.Both neutral and adaptive mtDNA mutations have becomeestablished in different populations. For example,an African variant at np 3594T defines a group of relatedmtDNA haplotypes (haplogroup) specific for Africa (Fig.1). This variant is common to African haplogroups L0,L1, and L2, which encompass 2/3 of all sub-SaharanAfrican mtDNAs, and are thus designated macro-haplogroupL (Fig. 2). Other variants include a polymorphismat np 7028T in COI that marks European haplogroupH; variants at np 6392 in COI and at np 10310 inCold Spring Harbor Symposia on Quantitative Biology, Volume LXVIII. © 2003 Cold Spring Harbor Laboratory Press 0-87969-709-1/04. 471