Suppressing the dark side of autophagy

Autophagy. 2019 Oct;15(10):1852-1853. doi: 10.1080/15548627.2019.1644077. Epub 2019 Jul 18.

Abstract

A wide variety of genetic, pharmacological and nutrient manipulations that extend lifespan in model organisms do so in a manner dependent upon increased autophagic flux. However, our recent findings suggest that when mitochondrial membrane integrity is compromised, macroautophagy/autophagy can be detrimental. In C. elegans lacking the serine/threonine kinase mechanistic target of rapamycin kinase complex 2 and its downstream effector SGK-1 (Serum- and Glucocorticoid-inducible Kinase homolog), lifespan is shortened in spite of increased levels of autophagy, whereas reducing autophagy restores normal lifespan. This is due to a concomitant defect in mitochondrial permeability in mutants defective in either SGK-1 or mechanistic target of rapamycin kinase complex 2, attributable to increased VDAC-1 (VDAC Voltage Dependent Anion Channel homolog) protein level. More generally, we find that induction of mitochondrial permeability reverses each and every tested paradigm of autophagy-dependent lifespan extension and, further, exacerbates ischemia-reperfusion injury. In this punctum, we discuss our finding that autophagy with increased mitochondrial permeability is a detrimental combination conserved from nematode to mammals.

Keywords: Aging; MTOR (mechanistic target of rapamycin kinase); MTOR complex 2 (MTORC2); SGK-1 (serum and glucocorticoid-regulated kinase); VDAC1 (voltage dependent anion channel 1); autophagy; ischemia/reperfusion injury; lifespan; mitochondrial permeability transition pore (mPTP).

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Humans
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
  • Mice
  • Mice, Knockout
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Permeability Transition Pore
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rict-1 protein, C elegans
  • Voltage-Dependent Anion Channel 1
  • Mechanistic Target of Rapamycin Complex 2
  • Protein-Serine-Threonine Kinases
  • Sgk-1 protein, C elegans
  • Sirolimus