Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence

By J. Passos, G. Saretzki, Shaheda S. Ahmed, Glyn Nelson, T. Richter, H. Peters, I. Wappler, M. Birket, Graham Harold, Karin Schaeuble and 3 more. PLoS Biology, 2007

762 citations recorded by the source corpus.

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.

Subfields: Aging, Endocrine and Autonomic Systems, Physiology

View Paper: https://www.semanticscholar.org/paper/859ba36ce619aad27e855985ce32f90b6c2c639a

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In Endocrine and Autonomic Systems

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Citations in the corpus

Cellular Senescence: A Translational Perspective (2017, background): “An essential part of SAMDappears to be a decrease in mitochondrial membrane potential related to mitochondrial membrane permeabilization (Passos et al., 2010, Passos et al., 2007).”
Chemokine signaling via the CXCR2 receptor reinforces senescence. (2008, background): “, 1999) and telomere-induced DNA damage during replicative senescence (Passos et al., 2007).”
Mitochondrial dysfunction in cell senescence and aging (2022, background): “This increase in oxidative stress leads to DNA damage, such as oxidized bases, single-strand breaks, double-strand breaks, and telomere shortening (4), activating p53 and pRb pathways and causing cell cycle arrest and senescence (28, 108).”
Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence (2012, neutral): “In young non-irradiated cells, as previously reporte”
Cellular Senescence: Defining a Path Forward. (2019, neutral): “Incontrast,senescentcellsoftenproducemoreROS,which can cause protein and lipid damage, as discussed in previous sections (see ‘‘Protein Damage’’ and ‘‘Lipid Damage’’), but also telomere shortening and DDR activation (Passos et al., 2007).”
Hallmarks of Cellular Senescence. (2018, neutral): “Mitochondrial dysfunction: condition in which the regulation of mitochondrial homeostasis, production of mitochondrial metabolites, mitochondrial membrane potential, and ROS generation are altered [95,143].”
DNA damage response and cellular senescence in tissues of aging mice (2009, methodology): “Accordingly, the average Pearson correlation coefficient in senescent late generation TERT) ⁄ ) MEFs was similar to that in senescent HDFs (Passos et al., 2007) but was significantly lower in senescent wtMEFs (Fig.”
Fat Tissue, Aging, and Cellular Senescence (2010, background): “The proportion of arrested cells in a population rises with increasing population doublings, rather than all cells becoming senescent at once (Martin-Ruiz et al., 2004; Passos et al., 2007).”
Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming (2011, background): “A mitochondria-poor capacity would enable iPSC to revert reactive oxygen species-dependent telomere shortening associated with cellular aging (Passos et al., 2007; Marion et al., 2009).”