TY - JOUR
T1 - Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence
AU - Passos, João F.
AU - Saretzki, Gabriele
AU - Ahmed, Shaheda
AU - Nelson, Glyn
AU - Richter, Torsten
AU - Peters, Heiko
AU - Wappler, Ilka
AU - Birket, Matthew J.
AU - Harold, Graham
AU - Schaeuble, Karin
AU - Birch-Machin, Mark A.
AU - Kirkwood, Thomas B.L.
AU - Von Zglinicki, Thomas
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pbio.0050110
DO - 10.1371/journal.pbio.0050110
M3 - Article
C2 - 17472436
AN - SCOPUS:34249028642
SN - 1544-9173
VL - 5
SP - 1138
EP - 1151
JO - PLoS biology
JF - PLoS biology
IS - 5
ER -