Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.

ABSTRACT

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations AMPK AMP-activated protein kinase; AOX alternative oxidase; Baf A bafilomycin A1; CI, respiratory complexes I; DCF-DA 2',7'-dichlordihydrofluorescein diacetate; DHE dihydroethidium; DSS dextran sodium sulfate; ΔΨmi mitochondrial inner membrane potential; EdU 5-ethynyl-2'-deoxyuridine; ETC electron transport chain; FA formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD inflammatory bowel disease; LC3B microtubule associated protein 1 light chain 3 beta; LPS lipopolysaccharide; MEFs mouse embryonic fibroblasts; MTORC1 mechanistic target of rapamycin kinase complex 1; mtDNA mitochondrial DNA; NAC N-acetyl cysteine; OXPHOS oxidative phosphorylation; PCs proliferating cells; PE phosphatidylethanolamine; PEITC phenethyl isothiocyanate; QCs quiescent cells; ROS reactive oxygen species; PLA2 phospholipase A2, WB western blot.