Protein phosphatase 2A-B56γ-Drp1-Rab7 signaling axis regulates mitochondria-lysosome crosstalk to sensitize the anti-cancer therapy of hepatocellular carcinoma

Mitochondria-lysosome crosstalk is an intercellular communication platform regulating mitochondrial quality control (MQC). Activated dynamin-related protein 1 (Drp1) with phosphorylation at serine 616 (p-Drp1(Ser616)) plays a critical role in mitophagy-dependent cell survival and anti-cancer therapy for hepatocellular carcinoma (HCC). However, the underlying mechanisms that p-Drp1(Ser616) involved in regulating mitochondria-lysosome crosstalk and mediating anti-HCC therapy remain unknown. HCC cells and mouse xenograft models were conducted to evaluate the relationship between p-Drp1(Ser616) and Ras-associated protein 7 (Rab7) and the underlying mechanism by protein phosphatase 2A (PP2A)-B56 gamma regulating mitophagy via dephosphorylation of p-Drp1(Ser616) in HCC. Herein, we found that Drp1 was frequently upregulated and was associated with poor prognosis in HCC. Mitochondrial p-Drp1(Ser616) was a novel inter-organelle tethering protein localized to mitochondrion and lysosome membrane contact sites (MCSs) via interaction with Rab7 to trigger an increase in the mitochondrialysosome crosstalk, resulting in PINK1-Parkin-dependent mitophagy and anti-apoptosis in HCC cells under the treatment of chemotherapy drugs. Moreover, we demonstrate that B56 gamma-mediated direct dephosphorylation of pDrp1Ser616 inhibited mitophagy and thus increased mitochondria-dependent apoptosis. Overall, our findings demonstrated that activation of B56 gamma sensitizes the anti-cancer effect of HCC chemoprevention via dephosphorylated regulation of p-Drp1(Ser616) in inhibiting the interaction between p-Drp1(Ser616) and Rab7, which may provide a novel mechanism underlying the theranostics for targeting intervention in HCC.

Automated summary

This study investigates the role of phosphorylated dynamin-related protein 1 (p-Drp1(Ser616)) in regulating mitochondria-lysosome crosstalk and mediating anti-hepatocellular carcinoma (HCC) therapy. The results demonstrate that p-Drp1(Ser616) interacts with Rab7 to trigger increased mitochondria-lysosome crosstalk and promote PINK1-Parkin-dependent mitophagy and anti-apoptosis in HCC cells. The study also shows that B56 gamma-mediated dephosphorylation of p-Drp1Ser616 inhibits mitophagy and increases mitochondria-dependent apoptosis.