Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.
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 [Ca(2+)]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.
Passos
João F
JF
Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, United Kingdom.
Saretzki
Gabriele
G
Ahmed
Shaheda
S
Nelson
Glyn
G
Richter
Torsten
T
Peters
Heiko
H
Wappler
Ilka
I
Birket
Matthew J
MJ
Harold
Graham
G
Schaeuble
Karin
K
Birch-Machin
Mark A
MA
Kirkwood
Thomas B L
TB
von Zglinicki
Thomas
T
D000367:Age Factors; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts; D005434:Flow Cytometry; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013269:Stochastic Processes; D016615:Telomere / Q000502:physiology*
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D002118:Calcium