Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Metab. 2013 Jun 4;17(6):954-964. doi: 10.1016/j.cmet.2013.04.003.
Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression.
活性氧（ROS）在衰老过程中发挥着复杂的作用，既有损伤作用又有信号功能。短暂地提高线粒体应激，包括线粒体 ROS（mtROS），会引发有益的反应，延长寿命。然而，这些适应性的、长寿信号通路仍然知之甚少。我们在这里表明，Tel1p 和 Rad53p，与哺乳动物 DNA 损伤反应激酶 ATM 和 Chk2 的同源物，介导了一种 hormetic mtROS 长寿信号，延长了酵母的生物钟寿命。这条途径以一种不同于核 DNA 损伤反应的方式感知 mtROS，最终通过特异性地使位于端粒外异染色质上的组蛋白去甲基化酶 Rph1p 失活，增强沉默蛋白 Sir3p 的结合，并抑制端粒外转录，从而赋予长寿。这些结果表明，存在保守的线粒体到细胞核应激信号通路，通过核基因表达的表观遗传调控来调节衰老。
