title: Partial uncoupling of oxidative phosphorylation induces premature senescence in human fibroblasts and yeast mother cells.
abstract: The mitochondrial theory of aging predicts that functional alterations in mitochondria leading to reactive oxygen species (ROS) production contribute to the aging process in most if not all species. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between impaired mitochondrial coupling and premature senescence. Chronic exposure of human fibroblasts to the chemical uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) led to a temporary, reversible uncoupling of oxidative phosphorylation. FCCP inhibited cell proliferation in a dose-dependent manner, and a significant proportion of the cells entered premature senescence within 12 days. Unexpectedly, chronic exposure of cells to FCCP led to a significant increase in ROS production, and the inhibitory effect of FCCP on cell proliferation was eliminated by the antioxidant N-acetyl-cysteine. However, antioxidant treatment did not prevent premature senescence, suggesting that a reduction in the level of oxidative phosphorylation contributes to phenotypical changes characteristic of senescent human fibroblasts. To assess whether this mechanism might be conserved in evolution, the influence of mitochondrial uncoupling on replicative life span of yeast cells was also addressed. Similar to our findings in human fibroblasts, partial uncoupling of oxidative phsophorylation in yeast cells led to a substantial decrease in the mother-cell-specific life span and a concomitant incrase in ROS, indicating that life span shortening by mild mitochondrial uncoupling may represent a "public" mechanism of aging.
authors: Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
authors: Petra
authors: P
authors: Stöckl
authors: Christina
authors: C
authors: Zankl
authors: Eveline
authors: E
authors: Hütter
authors: Hermann
authors: H
authors: Unterluggauer
authors: Peter
authors: P
authors: Laun
authors: Gino
authors: G
authors: Heeren
authors: Edith
authors: E
authors: Bogengruber
authors: Dietmar
authors: D
authors: Herndler-Brandstetter
authors: Michael
authors: M
authors: Breitenbach
authors: Pidder
authors: P
authors: Jansen-Dürr
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D019588:Aging, Premature / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D049109:Cell Proliferation; D019069:Cell Respiration; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000111:Acetylcysteine