Sustained inhibition of oxidative phosphorylation impairs cell proliferation and induces premature senescence in human fibroblasts.
The mitochondrial theory of aging predicts that functional alterations in mitochondria contribute to the aging process. Whereas this hypothesis implicates increased production of reactive oxygen species (ROS) as a driving force of the aging process, little is known about molecular mechanisms by which mitochondrial impairment might contribute to aging. 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 mitochondrial impairment and the appearance of a senescence-like phenotype in young cells. We found that treatment by antimycin A delays proliferation and induces premature senescence in a subset of the cells, associated with increased reactive oxygen species (ROS) production. Quenching of ROS by antioxidants did however not restore proliferation capacity nor prevent premature senescence. Premature senescence is also induced upon chronic exposure to oligomycin, irrespective of ROS production, and oligomycin treatment induced the up-regulation of the cdk inhibitors p16, p21 and p27, which are also up-regulated in replicative senescence. Thus, besides the well-established influence of ROS on proliferation and senescence, a reduction in the level of oxidative phosphorylation is causally related to reduced cell proliferation and the induction of premature senescence.
Stöckl
Petra
P
Institute for Biomedical Aging Research, Molecular and Cellular Biology, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria.
Hütter
Eveline
E
Zwerschke
Werner
W
Jansen-Dürr
Pidder
P
D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D000111:Acetylcysteine