DNA polymerase gamma (Polγ) deficiency triggers a selective mTORC2 prosurvival autophagy response via mitochondria-mediated ROS signaling

Abstract

Autophagy is a highly regulated evolutionarily conserved metabolic process induced by stress and energy deprivation. Here, we show that DNA polymerase gamma (Polγ) deficiency activates a selective prosurvival autophagic response via mitochondria-mediated reactive oxygen species (ROS) signaling and the mammalian target of rapamycin complex 2 (mTORC2) activities. In keratinocytes, Polγ deficiency causes metabolic adaptation that triggers cytosolic sensing of energy demand for survival. Knockdown of Polγ causes mitochondrial stress, decreases mitochondrial energy production, increases glycolysis, increases the expression of autophagy-associated genes, and enhances AKT phosphorylation and cell proliferation. Deficiency of Polγ preferentially activates mTORC2 formation to increase autophagy and cell proliferation, and knocking down Rictor abrogates these responses. Overexpression of Rictor, but not Raptor, reactivates autophagy in Polγ-deficient cells. Importantly, inhibition of ROS by a mitochondria-selective ROS scavenger abolishes autophagy and cell proliferation. These results identify Rictor as a critical link between mitochondrial stress, ROS, and autophagy. They represent a major shift in our understanding of the prosurvival role of the mTOR complexes and highlight mitochondria-mediated ROS as a prosurvival autophagy regulator during cancer development.

UVB-induced inactivation of manganese-containing superoxide dismutase promotes mitophagy via ROS-mediated mTORC2 pathway activation

“…6). Consistent with our previous findings that rictor plays a critical role in MEF cells during autophagy (19), we now have found that UVB treatment of rictor-deficient cells is unable to induce mitophagy (Fig. S2), suggesting a common mechanism in mitophagy.…”

“…Our previous studies have demonstrated a prosurvival role of mitochondrial injury (19). Because autophagy can lead to cell survival or death, we asked whether low-dose UVB radiation enhances cell survival.…”

Recent Insights into the Mitochondrial Role in Autophagy and Its Regulation by Oxidative Stress

“…By contrast, the pharmacological increase of mitochondrial ΔΨ counteracts the downregulation induced by PRKCB overexpression and rescues the normal rate of autophagy [95], most likely related to a high proton motive force-induced ROS production [96]. Moreover, perturbations of mitochondrial energy metabolism due to deficiencies of DNA polymerase gamma (Pol γ ) have been shown to increase O 2 •- and trigger prosurvival autophagy responses via Rictor-mediated mTORC2 activation [97]. In apparent contradiction, cells lacking mitochondrial DNA (mtDNA) have been reported as autophagy-deficient.…”

<p>Suppressing UVRAG Induces Radiosensitivity by Triggering Lysosomal Membrane Permeabilization in Hypopharyngeal Squamous Cell Carcinoma</p>

“…7 ROS and autophagy are two important factors involved in cellular stress response. 32 Previously, many studies reported that ROS was a key inducer of autophagy. 33 , 34 But recently, more and more studies showed that inhibition of autophagy could also upregulate the level of ROS.…”