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.

通过自噬（线粒体自噬）选择性降解受损线粒体被认为在细胞稳态中发挥重要作用。然而，人们对线粒体自噬对细胞生理学线粒体质量控制的分子机制和要求知之甚少。在这里，我们证明原代人类细胞维持由线粒体超氧化物信号传导引发的高度活跃的基础线粒体自噬。线粒体自噬被发现是由 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受到抑制，导致线粒体自噬的强烈关闭。抑制增殖细胞中的线粒体自噬足以触发衰老程序，而重新激活线粒体自噬对于 NAD 前体或雷帕霉素的抗衰老作用是必要的。此外，p62 靶向小分子重新激活线粒体自噬可以挽救细胞衰老的标志物，这使线粒体质量控制成为抗衰老干预措施的一个有前景的目标。