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Publication

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension.

Cell | 2019

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.

Pubmed ID: 30929899 RIS Download

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Associated grants

Agency: NIDDK NIH HHS, United States
Id: R01 DK101522
Agency: NIDDK NIH HHS, United States
Id: P30 DK040561
Agency: NIDDK NIH HHS, United States
Id: T32 DK007028
Agency: NIH HHS, United States
Id: P40 OD010440
Agency: NIA NIH HHS, United States
Id: R21 AG058038
Agency: NIDDK NIH HHS, United States
Id: P30 DK057521
Agency: NIA NIH HHS, United States
Id: R01 AG058256
Agency: NIA NIH HHS, United States
Id: R01 AG038664
Agency: NIA NIH HHS, United States
Id: P30 AG062421
Agency: NIDDK NIH HHS, United States
Id: K08 DK087941

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PRISM (tool)

RRID:SCR_005375

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.

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Caenorhabditis Genetics Center (tool)

RRID:SCR_007341

Center that acquires, maintains, and distributes genetic stocks and information about stocks of the small free-living nematode Caenorhabditis elegans for use by investigators initiating or continuing research on this genetic model organism. A searchable strain database, general information about C. elegans, and links to key Web sites of use to scientists, including WormBase, WormAtlas, and WormBook are available.

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