Oxidative stress and mitochondrial DNA mutations in human aging

Proc Soc Exp Biol Med. 1998 Jan;217(1):53-63. doi: 10.3181/00379727-217-44205.


The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the "Mitochondrial theory of aging."

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging / genetics
  • Aging / physiology*
  • Animals
  • DNA Damage
  • DNA, Mitochondrial / genetics*
  • DNA-Binding Proteins / metabolism
  • Free Radicals / metabolism
  • Histones / metabolism
  • Humans
  • Models, Biological
  • Oxidative Stress*
  • Oxygen Consumption
  • Reactive Oxygen Species / metabolism


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Free Radicals
  • Histones
  • Reactive Oxygen Species