Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila
Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila
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DOI：
10.1016/j.celrep.2019.06.070
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发表时间：
2019-07-23
期刊：
影响因子：
8.8
通讯作者：
Walker, David W.
中科院分区：
文献类型：
--
作者：
Aparicio, Ricardo;Rana, Anil;Walker, David W.
自噬是一种溶酶体降解途径，在健康和疾病中起着至关重要的作用。p62/SQSTM 1（下文称为p62）是一种自噬衔接蛋白，其可以穿梭泛素化的货物用于自噬降解。在这里，我们表明，从中年开始上调果蝇p62同源物ref（2）P/dp 62，可以延迟病理学的发生并延长健康的寿命。中年诱导dp 62改善蛋白质稳态，在老年苍蝇，在自噬依赖的方式。先前的研究已经报道，p62通过线粒体自噬介导功能障碍的线粒体的清除。然而，p62表达，线粒体稳态和衰老之间的因果关系仍然在很大程度上未被探索。我们发现，上调dp 62，在中年，促进线粒体分裂，促进线粒体自噬，并改善老年苍蝇的线粒体功能。最后，我们表明，线粒体分裂是需要中年dp 62诱导的抗衰老作用。我们的研究结果表明，p62是一个潜在的治疗靶点，以对抗衰老和延长老年哺乳动物的健康。
Autophagy, a lysosomal degradation pathway, plays crucial roles in health and disease. p62/SQSTM1 (hereafter p62) is an autophagy adaptor protein that can shuttle ubiquitinated cargo for autophagic degradation. Here, we show that upregulating the Drosophila p62 homolog ref(2)P/dp62, starting in midlife, delays the onset of pathology and prolongs healthy lifespan. Midlife induction of dp62 improves proteostasis, in aged flies, in an autophagy-dependent manner. Previous studies have reported that p62 plays a role in mediating the clearance of dysfunctional mitochondria via mitophagy. However, the causal relationships between p62 expression, mitochondrial homeostasis, and aging remain largely unexplored. We show that upregulating dp62, in midlife, promotes mitochondrial fission, facilitates mitophagy, and improves mitochondrial function in aged flies. Finally, we show that mitochondrial fission is required for the anti-aging effects of midlife dp62 induction. Our findings indicate that p62 represents a potential therapeutic target to counteract aging and prolong health in aged mammals.