Abstract：
Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
摘要：
通过自噬（mitophagy）选择性降解受损的线粒体被认为在细胞稳态中起重要作用。然而,对细胞生理学的分子机制和线粒体自噬对线粒体质量控制的要求知之甚少。这里,我们证明，原代人体细胞维持由线粒体超氧化物信号启动的高活性基底线粒体自噬。发现线粒体自噬是由PINK1/Parkin依赖性途径介导的，涉及p62作为选择性自噬受体（SAR）。重要的是,该途径在诱导细胞衰老和自然衰老的细胞中被抑制，导致有丝分裂的强大关闭。抑制增殖细胞中的线粒体自噬足以触发衰老程序，而线粒体自噬的重新激活对于NAD前体或雷帕霉素的抗衰老作用是必要的。此外，通过靶向p62的小分子重新激活线粒体自噬拯救了细胞衰老的标志物，将线粒体质量控制确立为抗衰老干预的有希望的目标。
