Journal
CELL
Volume 177, Issue 2, Pages 299-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.02.013
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Funding
- NIH/NIDDK [P30DK040561, P30DK057521]
- NIH Office of Research Infrastructure Programs [P40OD010440]
- C. elegans Knockout Consortium
- NIH [K08DK087941, R01DK101522, R01AG038664, R21AG058038]
- Ellison Medical Foundation New Scholar in Aging Award
- Howard M. Goodman Fellowship
- Charles H. Hood Foundation Child Health Research Award
- Weissman Family MGH Research Scholar Award
- Glenn Award for Research in Biological Mechanisms of Aging
- Ellison Medical Foundation/AFAR
- MGH ECOR Postdoctoral Fellowship
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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. clegans 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-depenant 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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