Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Autophagy / physiology
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Caenorhabditis elegans Proteins / physiology
  • Caloric Restriction
  • HEK293 Cells
  • Humans
  • Longevity / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membrane Transport Proteins / physiology*
  • Mitochondrial Membranes / physiology*
  • Mitochondrial Permeability Transition Pore
  • Permeability
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Reperfusion Injury / metabolism
  • Signal Transduction

Substances

  • Caenorhabditis elegans Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Protein-Serine-Threonine Kinases
  • Sgk-1 protein, C elegans