Mitochondrial DNA mutations in disease and aging

Abstract

The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

Figure 1.

Schematic representation of mammalian mtDNA. The double-stranded circular mammalian mtDNA molecule of ∼16.5 kb contains a single longer noncoding region, the displacement loop (D loop) region, harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (O_H). The origin of lagging strand replication (O_L) is embedded in a cluster of tRNA genes. The genes for the two rRNAs (12S and 16S rRNA), 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8), and 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A, and Q) are indicated by boxes. Illustration by Annika Röhl.

Figure 2.

Mitotic segregation of mtDNA. A single mutational event creates heteroplasmy in a cell, but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). There is no synchronization between cell division and mtDNA replication, and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle. Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA, and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function.

Figure 3.

Different levels at which purifying selection can occur in the maternal germline. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function, which, in turn, would lead to selection against and/or destruction of this mitochondrion. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. The colors indicate mutant (red) and wild-type (blue) mtDNA (top); respiratory chain–deficient (red) and normal (blue) mitochondria (middle); and respiratory chain–deficient (red) and normal (blue) cells (bottom).