Abstract
Mitophagy is an intracellular mechanism to maintain mitochondrial health by removing dysfunctional mitochondria. The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, whereas USP30 antagonizes Parkin-dependent mitophagy by removing ubiquitin from Parkin substrates. The AKT/mTOR signaling is a master regulator of cell proliferation, differentiation, apoptosis, and autophagy. Although mounting evidence suggests that perturbations in the AKT/mTOR signaling pathway may contribute to mitophagy regulation, the specific mechanisms between Parkin/USP30 and AKT/mTOR signaling have not been elucidated. In this study, we employ a set of genetic reagents to investigate the role of Parkin and USP30 in regulating the AKT/mTOR signaling during mitophagy. We demonstrated that, in the setting of mitochondrial stress, the AKT/mTOR signaling is regulated, at least in part, by the activity of Parkin and USP30. Parkin inhibits AKT/mTOR signaling following an in vitro mitochondrial stress, thereby promoting apoptosis. However, USP30 overexpression antagonizes the activity of Parkin to sustain AKT/mTOR activity and inhibit apoptosis. These findings provide new insights into Parkin and USP30’s role in apoptosis and suggest that inhibiting USP30 might provide a specific strategy to synergize with AKT/mTOR inhibitors in cancer treatment.
Highlights
Mitophagy, known as mitochondria-specific autophagy, is an evolutionarily conserved cellular mechanism to recycle specific mitochondria, by being encapsulated by the structurally doublemembrane autophagosome (Youle and Narendra, 2011; Dikic and Elazar, 2018; Saha et al, 2018; Khandia et al, 2019)
We demonstrated that Parkin and USP30 might regulate the AKT/mTOR signaling and cell survival during mitophagy, suggesting USP30 may serve as a potential drug target for leukemia treatment
Similar results were observed in Hela Parkin and Hela Parkin USP30 cells that lack AutophagyRelated-Gene 5 (ATG5). (Figure 2D). These results suggest that AKT/mTOR signaling is activated in response to mitochondrial stress, and can be regulated by Parkin and USP30
Summary
Known as mitochondria-specific autophagy, is an evolutionarily conserved cellular mechanism to recycle specific mitochondria, by being encapsulated by the structurally doublemembrane autophagosome (Youle and Narendra, 2011; Dikic and Elazar, 2018; Saha et al, 2018; Khandia et al, 2019). It remains possible that cells may become more vulnerable to specific mitochondrial stresses, and cell death may occur if the mitophagy response is too exuberant (Carroll et al, 2014; Liang et al, 2015; Wanderoy et al, 2020) Another significant mitophagy regulator is the AKT (Protein kinase B)/mTOR (The mechanistic target of rapamycin) signaling (Kim and Guan, 2015; Soutar et al, 2018; de la Cruz López et al, 2019). Previous studies indicate that the AKT/mTOR signaling inhibits mitophagy and promotes cell survival under mitochondrial stress (Akundi et al, 2012; Yang et al, 2017; Soutar et al, 2018; de la Cruz López et al, 2019; Wanderoy et al, 2020). We demonstrated that Parkin and USP30 might regulate the AKT/mTOR signaling and cell survival during mitophagy, suggesting USP30 may serve as a potential drug target for leukemia treatment
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