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Cell. 2019 Apr 4;177(2):299-314.e16. doi: 10.1016/j.cell.2019.02.013. Epub 2019 Mar 28.

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension.

Author information

1
Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
2
Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
3
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
4
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
5
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
6
MGH Biomedical Informatics Core and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
7
Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asoukas@mgh.harvard.edu.

Abstract

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.

KEYWORDS:

SGK; aging; autophagy; ischemia/reperfusion injury; longevity; mPTP; mTORC2; mitochondrial permeability

PMID:
30929899
PMCID:
PMC6610881
[Available on 2020-04-04]
DOI:
10.1016/j.cell.2019.02.013
[Indexed for MEDLINE]

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