The role of mitochondrial DNA mutations in mammalian aging

Abstract

Mitochondrial DNA (mtDNA) accumulates both base-substitution mutations and deletions with aging in several tissues in mammals. Here, we examine the evidence supporting a causative role for mtDNA mutations in mammalian aging. We describe and compare human diseases and mouse models associated with mitochondrial genome instability. We also discuss potential mechanisms for the generation of these mutations and the means by which they may mediate their pathological consequences. Strategies for slowing the accumulation and attenuating the effects of mtDNA mutations are discussed.

Figure 1. Human Disease-Associated Mutations in Genes Involved in mtDNA Replication and Maintenance

Mutations reported in POLG [,–162], TWINKLE (gene also known as PEO1) [,,,–167], and ANT1 (gene also known as SLC25A4) [35,40] proteins associated with human diseases. Mutations in black are associated with PEO, those in blue are associated with Alpers syndrome, red indicates mutations present in both PEO and Alpers, and green indicates mutations associated with other disorders. Italics indicate changes in DNA sequence. A) POLG. The light green and light blue segments represent the exonuclease and polymerase domains, respectively. Highly conserved motifs within each are shown as red segments. The POLG mutation figure is adapted from the Human DNA Polymerase Gamma Mutation Database maintained by the Mitochondrial Replication Group at the National Institute of Environmental Health Sciences (http://dir-apps.niehs.nih.gov/polg). B) TWINKLE. The pink domain is the primase-helicase linker region, as identified by homology to T7 phage protein [34]. C) ANT1. In addition to the pathogenic mutations shown within the protein, a 3.3-kb deletion upstream of ANT1 results in derepression of ANT1 and is associated with facioscapulohumeral muscular dystrophy [168]. Dup, duplication; fs, frameshift mutation; ins, insertion; *, termination codon

Figure 2. Multifactorial Events in Mammalian Aging

Oxidative stress is generated when reactive oxygen and nitrogen species (RONS) production exceeds protection from antioxidant defenses, and can lead to damaged proteins and mtDNA mutations. Replication errors are an additional source of mtDNA mutations. mtDNA mutations can result in reduction or loss of respiratory complex function and a pool of aberrant mitochondrial proteins. In certain situations (e.g., homoplasmic inherited mtDNA base-substitution mutations), specific mtDNA mutations could lead to increased oxidative stress, but this is not a feature of mice bearing random accumulations of mtDNA mutations. Activation of apoptosis could occur through mechanisms that sense energetic deficits or by signaling via rare misfolded proteins that might be capable of interacting with apoptotic regulators such as Bax or Bak. Prolonged activation of apoptotic cell death would gradually deplete tissues of both differentiated and possibily regenerative stem cells, leading to eventual tissue dysfunction and aging-related phenotypes. Additionally, chronic energetic deficiency in itself may contribute to altered tissue functioning with age. Inset: Polg^D257A mitochondrial mutator mouse (right) showing hair graying, alopecia, and kyphosis compared to a healthy age-matched control mouse. ETS, electron transport system; RONS, reactive oxygen and nitrogen species