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Mitochondrial respiration maintains autophagy to support stress resistance in quiescent cells

ABSTRACT: Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP and is required for pyrimidine nucleotide synthesis during proliferation. In contrast, the role of OXPHOS in post-mitotic cells, beyond its contribution to ATP production, is less understood. Here, we show that in non-proliferating cells, OXPHOS ensures protection against oxidative stress by sustaining autophagy. Autophagy is suppressed and oxidative stress resistance is compromised in OXPHOS-deficient non-proliferating cells in vitro and in TFAM knockout mice in vivo, while attenuation of autophagy in OXPHOS-functional cells phenocopies the effects of OXPHOS deficiency. Mechanistically, the regulation of the autophagy / stress response by OXPHOS does not require changes in gene expression, AMPK/mTOR1/ULK1 signaling or NADH levels. Instead, OXPHOS maintains ROS levels to prevent activation of ATG4, a ROS-activated inhibitor of autophagy. We propose that protection against oxidative stress via the ROS-ATG4 axis is a novel function of mitochondrial respiration in non-proliferating cells that may have consequences for cancer therapy and beyond.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146025 | GEO | 2022/01/07

REPOSITORIES: GEO

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Mitochondrial respiration is necessary to combat oxidative stress in quiescent cells

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