自噬
线粒体通透性转换孔
生物
细胞生物学
粒体自噬
MPTP公司
线粒体
品脱1
程序性细胞死亡
生物化学
细胞凋亡
内分泌学
多巴胺能
多巴胺
作者
Ben Zhou,Johannes Kreuzer,Caroline Kumsta,Lianfeng Wu,Kimberli J. Kamer,Lucydalila Cedillo,Yuyao Zhang,Sainan Li,Michael C. Kacergis,Christopher M. Webster,Géza Fejes-Tóth,Aniko Náray-Fejes-Tóth,Sudeshna Das,Malene Hansen,Wilhelm Haas,Alexander A. Soukas
出处
期刊:Cell
[Elsevier]
日期:2019-04-01
卷期号:177 (2): 299-314.e16
被引量:140
标识
DOI:10.1016/j.cell.2019.02.013
摘要
Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan. Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.
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