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Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging.
Chang Gung Med J. 2009 Mar-Apr; 32(2):113-32.CG

Abstract

Aging is a biological process that is characterized by the gradual loss of physiological function and increases in the susceptibility to disease of an individual. During the aging process, a wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) has been observed in somatic tissues of humans and animals. This is associated with the decline in mitochondrial respiratory function; excess production of the reactive oxygen species (ROS); increase in the oxidative damage to mtDNA, lipids and proteins in mitochondria; accumulation of point mutations and large-scale deletions of mtDNA; and altered expression of genes involved in intermediary metabolism. It has been demonstrated that the ROS may cause oxidative damage and mutations of mtDNA and alterations of the expression of several clusters of genes in aging tissues and senescent cells. We found that intracellular levels of hydrogen peroxide (H2O2) and oxidative damage to DNA in the tissue cells and skin fibroblasts of old donors were higher than those of young donors. In H2O2-induced senescent skin fibroblasts, we observed an increase in the protein expression and activity levels of manganese-dependent superoxide dismutase and a concurrent decrease in the activity of cytochrome c oxidase and the rate of oxygen consumption. Moreover, the mRNA and protein expression levels of pyruvate dehydrogenase (PDH) were decreased but those of PDH kinase and lactate dehydrogenase were increased in senescent skin fibroblasts. The changes in the expression of these enzymes suggest a metabolic shift from mitochondrial respiration to glycolysis as a major supply of ATP in aging human cells. On the other hand, recent studies on mitochondrial mutant mice, which carry a proofreading deficient subunit of DNA polymerase gamma, revealed that mtDNA mutations accumulated in somatic tissues in the mice that displayed prominent features of aging. Taken together, we suggest that the respiratory function decline and increase in the production of the ROS in mitochondria, accumulation of mtDNA mutation and oxidative damage, and altered expression of a few clusters of genes that culminated in the metabolic shift from mitochondrial respiration to glycolysis for major supply of ATP were key contributory factors in the aging process in the human and animals.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan. joeman@ym.edu.twNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19403001

Citation

Wei, Yau-Huei, et al. "Respiratory Function Decline and DNA Mutation in Mitochondria, Oxidative Stress and Altered Gene Expression During Aging." Chang Gung Medical Journal, vol. 32, no. 2, 2009, pp. 113-32.
Wei YH, Wu SB, Ma YS, et al. Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J. 2009;32(2):113-32.
Wei, Y. H., Wu, S. B., Ma, Y. S., & Lee, H. C. (2009). Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Medical Journal, 32(2), 113-32.
Wei YH, et al. Respiratory Function Decline and DNA Mutation in Mitochondria, Oxidative Stress and Altered Gene Expression During Aging. Chang Gung Med J. 2009 Mar-Apr;32(2):113-32. PubMed PMID: 19403001.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. AU - Wei,Yau-Huei, AU - Wu,Shi-Bei, AU - Ma,Yi-Shing, AU - Lee,Hsin-Chen, PY - 2009/5/1/entrez PY - 2009/5/1/pubmed PY - 2009/7/16/medline SP - 113 EP - 32 JF - Chang Gung medical journal JO - Chang Gung Med J VL - 32 IS - 2 N2 - Aging is a biological process that is characterized by the gradual loss of physiological function and increases in the susceptibility to disease of an individual. During the aging process, a wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) has been observed in somatic tissues of humans and animals. This is associated with the decline in mitochondrial respiratory function; excess production of the reactive oxygen species (ROS); increase in the oxidative damage to mtDNA, lipids and proteins in mitochondria; accumulation of point mutations and large-scale deletions of mtDNA; and altered expression of genes involved in intermediary metabolism. It has been demonstrated that the ROS may cause oxidative damage and mutations of mtDNA and alterations of the expression of several clusters of genes in aging tissues and senescent cells. We found that intracellular levels of hydrogen peroxide (H2O2) and oxidative damage to DNA in the tissue cells and skin fibroblasts of old donors were higher than those of young donors. In H2O2-induced senescent skin fibroblasts, we observed an increase in the protein expression and activity levels of manganese-dependent superoxide dismutase and a concurrent decrease in the activity of cytochrome c oxidase and the rate of oxygen consumption. Moreover, the mRNA and protein expression levels of pyruvate dehydrogenase (PDH) were decreased but those of PDH kinase and lactate dehydrogenase were increased in senescent skin fibroblasts. The changes in the expression of these enzymes suggest a metabolic shift from mitochondrial respiration to glycolysis as a major supply of ATP in aging human cells. On the other hand, recent studies on mitochondrial mutant mice, which carry a proofreading deficient subunit of DNA polymerase gamma, revealed that mtDNA mutations accumulated in somatic tissues in the mice that displayed prominent features of aging. Taken together, we suggest that the respiratory function decline and increase in the production of the ROS in mitochondria, accumulation of mtDNA mutation and oxidative damage, and altered expression of a few clusters of genes that culminated in the metabolic shift from mitochondrial respiration to glycolysis for major supply of ATP were key contributory factors in the aging process in the human and animals. SN - 2072-0939 UR - https://www.unboundmedicine.com/medline/citation/19403001/Respiratory_function_decline_and_DNA_mutation_in_mitochondria_oxidative_stress_and_altered_gene_expression_during_aging_ L2 - http://cgmj.cgu.edu.tw/3202/320201.pdf DB - PRIME DP - Unbound Medicine ER -