Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, 11221 Taipei, Taiwan.
Free Radic Biol Med. 2013 Oct;63:222-34. doi: 10.1016/j.freeradbiomed.2013.05.002. Epub 2013 May 7.
Progressive accumulation of defective mitochondria is a common feature of aged cells. SIRT3 is a NAD(+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. FOXO3 is a direct target of SIRT3 and functions as a forkhead transcription factor to govern diverse cellular responses to stress. Here we show that hydrogen peroxide induces SIRT3 to deacetylate FOXO3 at K271 and K290, followed by the upregulation of a set of genes that are essential for mitochondrial homeostasis (mitochondrial biogenesis, fission/fusion, and mitophagy). Consequently, SIRT3-mediated deacetylation of FOXO3 modulates mitochondrial mass, ATP production, and clearance of defective mitochondria. Thus, mitochondrial quantity and quality are ensured to maintain mitochondrial reserve capacity in response to oxidative damage. Maladaptation to oxidative stress is a major risk factor underlying aging and many aging-related diseases. Hence, our finding that SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative stress provides a possible direction for aging-delaying therapies and disease intervention.
线粒体缺陷的逐渐积累是衰老细胞的一个共同特征。SIRT3 是一种 NAD(+)依赖的蛋白去乙酰化酶，可响应热量限制和应激调节线粒体功能和代谢。FOXO3 是 SIRT3 的直接靶标，作为叉头转录因子发挥作用，调节细胞对压力的多种反应。在这里，我们表明过氧化氢诱导 SIRT3 对 FOXO3 进行 K271 和 K290 去乙酰化，随后上调一组对线粒体动态平衡（线粒体生物发生、分裂/融合和线粒体自噬）至关重要的基因。因此，SIRT3 介导的 FOXO3 去乙酰化调节线粒体质量、ATP 产生和缺陷线粒体的清除。因此，为了应对氧化损伤，线粒体的数量和质量得到了保证，以维持线粒体的储备能力。不能适应氧化应激是衰老和许多与衰老相关疾病的主要危险因素。因此，我们发现 SIRT3 通过去乙酰化 FOXO3 来保护线粒体免受氧化应激，为延缓衰老和疾病干预的治疗提供了一个可能的方向。
