Cell, 2019-04, Vol.177 (2), p.299-314.e16
2019
Details
- Autor(en) / Beteiligte
- Titel
- Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension
- Ist Teil von
- Cell, 2019-04, Vol.177 (2), p.299-314.e16
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- 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. [Display omitted] •SGK1 regulates autophagy in both C. elegans and mammalian cells•Elevated autophagy and mPTP opening shorten lifespan in sgk-1/mTORC2 mutant worms•SGK-1 phosphorylates mPTP component VDAC1 on Ser104, promoting its degradation•Loss of SGK function exaggerates mPTP-dependent hepatic ischemia/reperfusion injury The role of autophagy in lifespan extension depends on modulation of mitochondrial permeability via the action of the kinase SGK1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2019.02.013Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6610881
- Format
- –
- Schlagworte
- aging, Aging - metabolism, Animals, autophagy, Autophagy - physiology, Caenorhabditis elegans - metabolism, Caenorhabditis elegans Proteins - genetics, Caenorhabditis elegans Proteins - metabolism, Caenorhabditis elegans Proteins - physiology, Caloric Restriction, HEK293 Cells, Humans, ischemia/reperfusion injury, longevity, Longevity - physiology, Male, Mice, Mice, Knockout, Mitochondria, Mitochondrial Membrane Transport Proteins - metabolism, Mitochondrial Membrane Transport Proteins - physiology, Mitochondrial Membranes - physiology, mitochondrial permeability, mPTP, mTORC2, Permeability, Primary Cell Culture, Protein-Serine-Threonine Kinases - genetics, Protein-Serine-Threonine Kinases - metabolism, Protein-Serine-Threonine Kinases - physiology, Reperfusion Injury - metabolism, SGK, Signal Transduction