V体育官网入口 - Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

Review
. 2007 Feb 23;3(2):e24.
doi: 10.1371/journal.pgen.0030024.

The role of mitochondrial DNA mutations in mammalian aging

Gregory C Kujoth  1 , Patrick C Bradshaw, Suraiya Haroon, Tomas A Prolla
Affiliations
Review

The role of mitochondrial DNA mutations in mammalian aging

Gregory C Kujoth et al. PLoS Genet. .

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 VSports手机版. Strategies for slowing the accumulation and attenuating the effects of mtDNA mutations are discussed. .

PubMed Disclaimer

Conflict of interest statement

Competing interests. GCK and TAP were awarded a United States patent (7,126,040) for the PolgD257A mouse model described here. TAP is a partial owner and scientific consultant for LifeGen Technologies, specializing in the application of DNA microarray analysis to analyzing nutraceutical interventions in aging V体育安卓版.

Figures

Figure 1
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
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: PolgD257A 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
See this image and copyright information in PMC

References

    1. Zhang C, Liu VW, Addessi CL, Sheffield DA, Linnane AW, et al. Differential occurrence of mutations in mitochondrial DNA of human skeletal muscle during aging. Hum Mutat. 1998;11:360–371. - PubMed
    1. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science. 1999;286:774–779. - PubMed
    1. Wang Y, Michikawa Y, Mallidis C, Bai Y, Woodhouse L, et al. Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc Natl Acad Sci U S A. 2001;98:4022–4027. - "VSports最新版本" PMC - PubMed
    1. Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, et al. Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci U S A. 2003;100:1116–1121. - PMC - PubMed
    1. Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet. 2002;11:133–145. - PubMed

"VSports最新版本" LinkOut - more resources