Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging.
Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging.
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DOI：
10.1016/j.celrep.2017.10.038
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发表时间：
2017-11-07
期刊：
影响因子：
8.8
通讯作者：
Morimoto RI
中科院分区：
文献类型：
--
作者：
Labbadia J;Brielmann RM;Neto MF;Lin YF;Haynes CM;Morimoto RI
在秀丽隐杆线虫中，热休克反应（HSR）的程序性抑制伴随着向生殖成熟的过渡，使细胞容易受到环境应激和蛋白质聚集的影响。为了确定驱动这一事件的因素，我们进行了一个公正的遗传筛选的抑制应激反应，并确定了线粒体电子传递链（ETC）作为一个中央调节器的年龄相关的下降的HSR和胞质蛋白质。通过遗传调节或暴露于线粒体靶向外源性物质，ETC活性的轻度下调通过增加HSF-1结合和RNA聚合酶II在HSF-1靶基因的募集来维持成年期的HSR。这导致细胞质蛋白质稳态的稳健恢复，并在生命后期增加活力，而不会对繁殖力产生不利影响。我们认为，低水平的线粒体压力调节细胞质蛋白质稳态和健康寿命在老化过程中，通过协调长期活动的HSF-1的条件排除最佳健身。
In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance, and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild down-regulation of ETC activity, either by genetic modulation or exposure to mitochondria targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes. This resulted in a robust restoration of cytoplasmic proteostasis and increased vitality later in life, without detrimental effects on fecundity. We propose that low levels of mitochondrial stress regulate cytoplasmic proteostasis and healthspan during aging by coordinating the long-term activity of HSF-1 with conditions preclusive to optimal fitness.
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