Oxidative Damage and Mutation to Mitochondrial DNA and Age-dependent Decline of Mitochondrial Respiratory Functiona

Authors

  • YAU-HUEI WEI,

    Corresponding author
    1. Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
    Search for more papers by this author
  • CHING-YOU LU,

    1. Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
    Search for more papers by this author
  • HSIN-CHEN LEE,

    1. Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
    Search for more papers by this author
  • CHENG-YOONG PANG,

    1. Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
    Search for more papers by this author
  • YI-SHING MA

    1. Department of Biochemistry and Center for Cellular and Molecular Biology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
    Search for more papers by this author

  • a

    The work described in this article was supported by research Grants from the National Science Council (NSC86-2314-B010-09 and NSC87-2314-B010-089) and the National Health Research Institutes (DOH87-HR-505), Executive Yuan, Republic of China. One of the authors Yau-Huei Wei, wishes to express his appreciation to the National Science Council for its considerable support of the studies on the miotochondrial role in human aging.

Tel: 866-2-28267118; fax: 886-2-28264843; e-mail: joeman@mailsrv.ym.edu.tw

Abstract

ABSTRACT: Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age-dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA-binding proteins, is susceptible to oxidative damage by the ever-increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8-hydroxy-2′-deoxyguanosine) and large-scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA-encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age-dependent progression of the clinical course of mitochondrial diseases.

Ancillary