Human mitochondrial DNA: roles of inherited and somatic mutations

Abstract

Mutations in the human mitochondrial genome are known to cause an array of diverse disorders, most of which are maternally inherited, and all of which are associated with defects in oxidative energy metabolism. It is now emerging that somatic mutations in mitochondrial DNA (mtDNA) are also linked to other complex traits, including neurodegenerative diseases, ageing and cancer. Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis.

Figure 1. Mitochondrial DNA and the human respiratory chain/oxidative phosphorylation system

a | The human mitochondrial genome. The 37 mitochondrial DNA (mtDNA)-encoded genes include seven subunits of complex I (ND1, 2, 3, 4, 4L, 5 and 6), one subunit of complex III (cytochrome b (Cyt b)), three subunits of complex IV (Cyt c oxidase (COX) I, II and III), two subunits of complex V (A6 and A8), two rRNAs (12S and 16S) and 22 tRNAs (one-letter code). Also shown are the origins of replication of the heavy strand (O_H) and the light strand (O_L), and the promoters of transcription of the heavy strand (HSP) and light strand (LSP). b | Oxidative phosphorylation (OXPHOS) complexes. The system is comprised of complex I (NADH dehydrogenase-CoQ reductase), complex II (succinate dehydrogenase), complex III (ubiquinone-Cyt c oxidoreductase), complex IV (COX) and complex V (ATP synthase; F₀ and F₁ denote the proton-transporting and catalytic subcomplexes, respectively), plus two electron carriers, coenzyme Q (CoQ; also called ubiquinone) and Cyt c. Complexes I–IV pump NADH- and FADH₂-derived protons (produced by the tricarboxylic acid (TCA) cycle and the β-oxidation ‘spiral’) from the matrix across the mitochondrial inner membrane to the intermembrane space to generate a proton gradient while at the same time transferring electrons to molecular oxygen to produce water. The proton gradient, which makes up most of the mitochondrial transmembrane potential (Δψ_m), is used to do work by being dissipated across the inner membrane in the opposite direction through the fifth complex (ATP synthase), thereby generating ATP from ADP and free phosphate. Complexes I, III, IV and V contain both mtDNA- and nuclear DNA (nDNA)-encoded subunits, whereas complex II, which is also part of the TCA cycle, has only nDNA-encoded subunits. Note that CoQ also receives electrons from dihydroorotate dehydrogenase (DHOD), an enzyme of pyrimidine synthesis. Polypeptides encoded by nDNA are in blue (except for DHOD, which is in pink); those encoded by mtDNA are in colours corresponding to the colours of the polypeptide-coding genes (shown in a). The ‘assembly’ proteins are all nDNA-encoded. IMS, intermembrane space; MIM, mitochondrial inner membrane. Part a is modified from REF. © (2006) Wiley.

Figure 2. Example of the potential to amplify inadvertently a nucleus-embedded mitochondrial sequence

Comparison of a region of the 16S rRNA gene within authentic mitochondrial DNA (mtDNA) (top lines; numbering according to the standard ‘Cambridge’ mtDNA sequence) to that of a nucleus-embedded mitochondrial sequence (NUMT) located on chromosome 17p11.2 (bottom lines; genome numbering according to the February 2009 release of the human genome (GRCh37/hg19)). The primer pairs used (Forward and Reverse 1, and Forward and Reverse 2) have the potential to amplify both mtDNA and the NUMT. Sequence differences between mtDNA (black) and NUMT DNA (red) are shown in bold.