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Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension
Ben Zhou1, Johannes Kreuzer2, Caroline Kumsta3
1Department 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.
Cell
|April 2, 2019
Summary
Autophagy can shorten lifespan when mitochondrial permeability is high, as seen in sgk-1 mutants. Lowering mitochondrial permeability or autophagy levels restores longevity, highlighting its crucial role in aging.
Area of Science:
- Cellular Biology
- Aging Research
- Mitochondrial Biology
Background:
- Autophagy is widely considered beneficial for longevity.
- However, its detrimental effects in specific contexts are not well understood.
Purpose of the Study:
- To investigate the role of mitochondrial permeability in determining autophagy's impact on lifespan.
- To explore the mechanisms underlying autophagy's dual role in aging.
Main Methods:
- Utilized Caenorhabditis elegans (C. elegans) sgk-1 mutants and liver-specific Sgk knockout mice.
- Manipulated autophagy levels and mitochondrial permeability transition pore (mPTP) opening.
- Examined lifespan, autophagy, and mitochondrial permeability in various aging models.
Main Results:
- Elevated autophagy shortened lifespan in C. elegans lacking sgk-1 due to increased mitochondrial permeability.
- Reducing autophagy or mPTP opening in sgk-1 mutants restored normal lifespan.
- Low mitochondrial permeability is essential for autophagy-dependent lifespan extension across different paradigms.
- Genetically induced mPTP opening blocked lifespan extension from caloric restriction or germline stem cell loss.
- Mammalian studies showed enhanced autophagy and mPTP opening in liver-specific Sgk knockout mice, leading to injury.
Conclusions:
- Mitochondrial permeability is a critical determinant of whether autophagy promotes or harms longevity.
- Targeting mitochondrial permeability may be a strategy to harness autophagy's benefits for aging and disease.
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