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

Suppressing the dark side of autophagy.

Author information

1
Department of Medicine, Diabetes Unit, and Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School , Boston , MA , USA.

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)

PMID:
31313620
PMCID:
PMC6735539
[Available on 2020-07-18]
DOI:
10.1080/15548627.2019.1644077

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