Mitochondrial respiration supports autophagy to provide stress resistance during quiescence

• DOI: 10.1080/15548627.2022.2038898
• Publication Date: 2022-03-08T16:49:26Z
• Authors: Silvia Magalhaes-...; Jan Blecha; Ravindra Naraine; Jana Mikesova; Pavel Abaffy; Alena Pecinova; Mirko Milosevic; Romana Bohuslavova; Jan Prochazka; Shawez Khan; Eliska Novotna; Radek Sindelka; Radek Machan; Mieke Dewerchin; Erik Vlcak; Joanna Kalucka; Sona Stemberkova ...; Ales Benda; Jermaine Goveia; Tomas Mracek; Cyril Barinka; Peter Carmeliet; Jiri Neuzil; Katerina Rohlenova; Jakub Rohlena
• Keywords: Mitochondrial ROS; Sequestosome 1

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of quiescence, beyond ATP production, is not well understood. Using mouse models inducible deficiency in all cell types or specifically vascular endothelium that negligibly relies on OXPHOS-derived we show selectively quiescence provides stress resistance by supporting macroautophagy/autophagy. Mechanistically, constitutively low levels endogenous ROS induce autophagy via attenuation ATG4B activity, which protection from insult. Physiologically, OXPHOS-autophagy system (i) protects healthy tissue toxicity ROS-based anticancer therapy, and (ii) endothelium, ameliorating systemic LPS-induced inflammation as inflammatory bowel disease. Hence, cells acquired mitochondria evolution to profit metabolism, built an autophagy-based ROS-induced protective mechanism guard against associated with function 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: disease; LC3B: microtubule 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: embryonic fibroblasts; MTORC1: mechanistic target rapamycin kinase complex 1; mtDNA: DNA; NAC: N-acetyl cysteine; OXPHOS: phosphorylation; PCs: proliferating PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.