Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.
Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence.
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DOI：
10.1371/journal.pbio.0050110
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发表时间：
2007-05
期刊：
影响因子：
9.8
通讯作者：
von Zglinicki T
中科院分区：
文献类型：
--
作者：
Passos JF;Saretzki G;Ahmed S;Nelson G;Richter T;Peters H;Wappler I;Birket MJ;Harold G;Schaeuble K;Birch-Machin MA;Kirkwood TB;von Zglinicki T
衰老是一个固有的随机过程，其标志是生物体，细胞类型和克隆种群之间的异质性，即使在相同的环境中。原代人类细胞的复制寿命依赖于端粒;然而，其异质性尚不清楚。我们发现，线粒体超氧化物的生产增加与复制年龄在人类成纤维细胞，尽管自适应UCP-2依赖的线粒体解偶联。这种线粒体功能障碍伴随着受损的[Ca 2 +]i稳态和衰老细胞中逆行反应的其他指标。人成纤维细胞的复制性衰老被轻度线粒体解偶联延迟。解偶联减少线粒体超氧化物生成，减缓端粒缩短，并延迟端粒γ-H2 A. X焦点的形成。这表明线粒体产生的活性氧（ROS）作为复制衰老的原因之一。通过从年轻的增殖成纤维细胞培养物中分选早期衰老（SES）细胞，我们表明SES细胞具有较高的ROS水平、功能失调的线粒体、较短的端粒和端粒γ-H2 A. X灶。我们认为，线粒体活性氧是一个主要的决定因素，端粒依赖性衰老在单细胞水平，负责细胞间的变化，在复制寿命。在有限数量的细胞分裂后，体细胞失去增殖能力，称为细胞复制性衰老。衰老是由染色体末端（端粒）的DNA序列丢失引发的，通常被视为有规律的“生物钟”的一个例子。然而，细胞衰老是异质性的，在个体细胞谱系之间具有很大的寿命差异。这种异质性显然与应激有关，特别是氧化应激。然而，目前尚不清楚压力诱导的“过早”衰老是否涉及端粒或由端粒无关的DNA损伤反应引起。线粒体是生理条件下细胞内活性氧最重要的来源。我们发现，当细胞接近衰老时，线粒体功能恶化，导致ROS产生增加。延缓线粒体功能障碍导致复制性衰老的延迟和端粒缩短的减缓。从年轻培养物中筛选出的早衰细胞显示线粒体功能障碍，氧化应激增加和端粒缩短。我们认为，复制端粒依赖性衰老不是“时钟”，而是一个随机过程，主要由随机线粒体功能障碍触发。线粒体解偶联被用来研究端粒长度、活性氧的产生和复制性衰老之间的关系。
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. After a limited number of cell divisions, somatic cells lose the capacity for proliferation, called cellular replicative senescence. Senescence, which is triggered by the loss of DNA sequences at the ends of chromosomes (telomeres), is often seen as an example of a regular “biological clock.” However, cell senescence is heterogeneous, with large differences in lifespan between individual cell lineages. This heterogeneity is clearly related to stress, specifically oxidative stress. It was not known, however, whether stress-induced “premature” senescence involves telomeres or is caused by telomere-independent DNA damage responses. Mitochondria are the most important source of reactive oxygen species (ROS) in cells under physiological conditions. We found that mitochondrial function deteriorated while cells approached senescence, leading to increased ROS production. Delaying mitochondrial dysfunction led to postponed replicative senescence and slowing of telomere shortening. Prematurely senescing cells sorted out of young cultures displayed mitochondrial dysfunction, increased oxidative stress, and short telomeres. We propose that replicative telomere-dependent senescence is not “clocked,” but rather is a stochastic process triggered largely by random mitochondrial dysfunction. Mitochondrial uncoupling is used to study the relationship between telomere length, the production of reactive oxygen species, and replicative senescence.
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影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
11.4
作者：
Biswas, G;Adebanjo, OA;Avadhani, NG
通讯作者：
Avadhani, NG
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
影响因子：
3.4
作者：
Costes, SV;Daelemans, D;Lockett, S
通讯作者：
Lockett, S