A role for mitochondria as potential regulators of cellular life span

Biochem Biophys Res Commun. 2002 Jun 7;294(2):245-8. doi: 10.1016/S0006-291X(02)00464-3.

Abstract

We demonstrate that by simply raising extracellular pyruvate levels, and hence increasing metabolic supply, human diploid fibroblasts undergo a concentration-dependent induction of cellular senescence. Fibroblasts treated with pyruvate undergo a rapid growth arrest accompanied by elevated levels of the cell-cycle regulatory molecules p53, p21, and p16. These cells also exhibit a rise in mitochondrial oxidant production and a fall in intracellular glutathione levels. Exposure of pyruvate treated cells to the antioxidant and glutathione precursor N-acetylcysteine restores cell growth and reverses the increase in senescence-associated beta-galactosidase activity. Similarly, we demonstrate that by increasing mitochondrial number via retroviral-mediated expression of the mitochondrial biogenesis regulator PGC-1 there is also a reduction in cell growth and the more rapid induction of senescence. These results suggest that mitochondria appear to play a central role in regulating cellular life span.

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Cell Division / drug effects
  • Cell Line
  • Cellular Senescence / drug effects*
  • Cellular Senescence / physiology
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Dose-Response Relationship, Drug
  • Energy Metabolism
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Humans
  • Mitochondria / metabolism*
  • Oxidants / metabolism
  • Pyruvic Acid / metabolism
  • Pyruvic Acid / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism
  • beta-Galactosidase / metabolism

Substances

  • Antioxidants
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Oxidants
  • Tumor Suppressor Protein p53
  • Pyruvic Acid
  • beta-Galactosidase
  • Acetylcysteine