Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence

João F. Passos, Gabriele Saretzki, Shaheda Ahmed, Glyn Nelson, Torsten Richter, Heiko Peters, Ilka Wappler, Matthew J. Birket, Graham Harold, Karin Schaeuble, Mark A. Birch-Machin, Thomas B.L. Kirkwood, Thomas Von Zglinicki

Research output: Contribution to journalArticle

408 Scopus citations

Abstract

Aging is an inherently stochastic process, and its hallmark is heterogeneity between organisms, cell types, and clonal populations, even in identical environments. The replicative lifespan of primary human cells is telomere dependent; however, its heterogeneity is not understood. We show that mitochondrial superoxide production increases with replicative age in human fibroblasts despite an adaptive UCP-2-dependent mitochondrial uncoupling. This mitochondrial dysfunction is accompanied by compromised [Ca2+] i homeostasis and other indicators of a retrograde response in senescent cells. Replicative senescence of human fibroblasts is delayed by mild mitochondrial uncoupling. Uncoupling reduces mitochondrial superoxide generation, slows down telomere shortening, and delays formation of telomeric γ-H2A.X foci. This indicates mitochondrial production of reactive oxygen species (ROS) as one of the causes of replicative senescence. By sorting early senescent (SES) cells from young proliferating fibroblast cultures, we show that SES cells have higher ROS levels, dysfunctional mitochondria, shorter telomeres, and telomeric γ-H2A.X foci. We propose that mitochondrial ROS is a major determinant of telomere-dependent senescence at the single-cell level that is responsible for cell-to-cell variation in replicative lifespan.

Original languageEnglish (US)
Pages (from-to)1138-1151
Number of pages14
JournalPLoS biology
Volume5
Issue number5
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Passos, J. F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Wappler, I., Birket, M. J., Harold, G., Schaeuble, K., Birch-Machin, M. A., Kirkwood, T. B. L., & Von Zglinicki, T. (2007). Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS biology, 5(5), 1138-1151. https://doi.org/10.1371/journal.pbio.0050110