Mitochondria Damage Checkpoint, Aging, and Cancer
Mitochondria Damage Checkpoint, Aging, and Cancer
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DOI：
10.1196/annals.1354.022
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Singh, Keshav K.
中科院分区：
文献类型：
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作者：
Singh, Keshav K.
越来越多的证据支持线粒体功能随着年龄的增长而逐渐下降。线粒体是细胞中产生活性氧簇（ROS）的主要场所;因此，线粒体功能的逐渐下降很可能是由于随着年龄的增长氧化损伤的积累。尽管有这个概念，线粒体在细胞衰老中的作用在很大程度上被忽视了。我们使用来自多种组织类型的线粒体基因敲除细胞（rho（0））的研究表明，线粒体功能的丧失导致细胞周期停滞、细胞衰老和致瘤表型。根据这些和早期的研究，我们假设在人类细胞中存在线粒体损伤检查点（mitocheckpoint）。线粒体检查点允许细胞在细胞周期中停滞，以便将线粒体功能修复/恢复到正常水平。在线粒体受到压倒性的、持续的或严重的损伤时，线粒体检查点机制可能会使细胞衰老。因此，细胞衰老可以作为细胞决定启动程序性细胞死亡之前的另一个检查点，导致组织和器官的老化。或者，突变发生在线粒体和/或核DNA中，导致肿瘤发生。
There is growing evidence supporting the progressing decline in mitochondrial function with age. Mitochondria are the major site of reactive oxygen species (ROS) production in the cell; therefore it is likely that progressive decline in mitochondrial function is due to the accumulation of oxidative damage with age. Despite this notion, a role for mitochondria in cellular senescence has been largely ignored. Our studies using mitochondrial gene knockout cells (rho(0)) from a variety of tissue types demonstrate that loss of mitochondrial function leads to cell cycle arrest, cellular senescence, and tumorigenic phenotype. In light of these and earlier studies we hypothesize the existence of a mitochondria damage checkpoint (mitocheckpoint) in human cells. Mitocheckpoint permits cells to arrest in the cell cycle in order to repair/restore mitochondrial function to the normal level. Upon overwhelming, persistent, or severe damage to mitochondria, mitocheckpoint machinery may allow cells to undergo senescence. Thus cellular senescence may function as another checkpoint before cells decide to initiate programmed cell death resulting in aging of tissues and organs. Alternatively, mutations occur in the mitochondrial and/or nuclear DNA, resulting in tumorigenesis.