Autophagy promotes mammalian survival by suppressing oxidative stress and p53

Abstract

Autophagy captures intracellular components and delivers them to lysosomes for degradation and recycling. Conditional autophagy deficiency in adult mice causes liver damage, shortens life span to 3 mo due to neurodegeneration, and is lethal upon fasting. As autophagy deficiency causes p53 induction and cell death in neurons, we sought to test whether p53 mediates the lethal consequences of autophagy deficiency. Here, we conditionally deleted Trp53 (p53 hereafter) and/or the essential autophagy gene Atg7 throughout adult mice. Compared with Atg7 Δ/Δ mice, the life span of Atg7 Δ/Δ p53 Δ/Δ mice was extended due to delayed neurodegeneration and resistance to death upon fasting. Atg7 also suppressed apoptosis induced by p53 activator Nutlin-3, suggesting that autophagy inhibited p53 activation. To test whether increased oxidative stress in Atg7 Δ/Δ mice was responsible for p53 activation, Atg7 was deleted in the presence or absence of the master regulator of antioxidant defense nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 −/− Atg7 Δ/Δ mice died rapidly due to small intestine damage, which was not rescued by p53 codeletion. Thus, Atg7 limits p53 activation and p53-mediated neurodegeneration. In turn, NRF2 mitigates lethal intestine degeneration upon autophagy loss. These findings illustrate the tissue-specific roles for autophagy and functional dependencies on the p53 and NRF2 stress response mechanisms.

Autophagy Compensates for Lkb1 Loss to Maintain Adult Mice Homeostasis and Survival

“…Moreover, AMPK and autophagy were activated in Lkb1-deficient lung tumors (19,20). p53 is activated upon autophagy deletion, leading to increased apoptotic rates in mouse liver and brain, impairing the overall mouse homeostasis (36). A recent study shows that Atg7 specific deletion in Lgr5 + epithelium cells promotes p53-induced apoptosis, leading to impaired integrity of intestinal barrier during stress (33).…”

“…Given that autophagy drives an inhibitory role towards p53 activation (12,35,36), we expected to observe an increased p53 activation in autophagy-deficient mouse tissues. Indeed, IHC staining for p53 showed that the frequency of nuclear p53 was significantly higher in most tissues of Atg7 -/-;Lkb1 -/mice compared with Lkb1 -/mice or WT control mice after short-term deletion of the genes ( Fig.…”

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

“…While NRF2 activation by p62 in cancers is protumorigenic, NRF2 also plays a critical role in the cellular response to autophagy deficiency in normal tissues. NRF2 protected against small intestine damage and animal death following whole body Atg7 and Trp53 deletion [ 127 ], suggesting that NRF2 activation by p62 is important for cellular adaptation and homeostatic control. NRF2 can regulate the expression of certain proteasome subunits, which may explain how NRF2 is protective in the context of autophagy impairment [ 128 ].…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…These effects are mostly bound to Nrf2 activation, which acts as a hub in bridging reduction of oxidative stress, autophagy induction, and inhibition of neuronal apoptosis. In line with this, increased oxidative stress occurs in the brain of mice featuring impaired autophagy due to Atg7 ablation, which in turn promotes p53 activation and neurodegeneration [ 166 ]. When Atg7 is deleted concomitantly with Nrf2, animals’ death rapidly occurs, indicating an interdependency between autophagy, p53, and Nrf2 stress response mechanisms [ 166 ].…”

“…In line with this, increased oxidative stress occurs in the brain of mice featuring impaired autophagy due to Atg7 ablation, which in turn promotes p53 activation and neurodegeneration [ 166 ]. When Atg7 is deleted concomitantly with Nrf2, animals’ death rapidly occurs, indicating an interdependency between autophagy, p53, and Nrf2 stress response mechanisms [ 166 ]. The interplay between autophagy and Nrf2 involves also molecular mechanisms that may be independent of redox status.…”