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

Lookup NU author(s): Dr Joao Passos, Dr Gabriele Saretzki, Dr Saeed Ahmed, Dr Glyn Nelson, Torsten Richter, Dr Heiko Peters, Ilka Wappler, Matthew Birket, Graham Harold, Professor Mark Birch-Machin, Emeritus Professor Thomas Kirkwood, Professor Thomas von Zglinicki

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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 gamma-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 gamma-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.


Publication metadata

Author(s): Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TBL, von Zglinicki T

Publication type: Article

Publication status: Published

Journal: PLoS Biology

Year: 2007

Volume: 5

Issue: 5

Pages: 1138-1151

ISSN (print): 1544-9173

ISSN (electronic): 1545-7885

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pbio.0050110

DOI: 10.1371/journal.pbio.0050110


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