PINK1 and BNIP3 mitophagy inducers have an antagonistic effect on Rbf1-induced apoptosis in Drosophila

Abstract The structure and function of the mitochondrial network are finely regulated. Among the proteins involved in these regulations, mitochondrial dynamics actors have been reported to regulate the apoptotic process. We show here in the Drosophila model that the mitophagy inducers, PINK1 (PTEN- induced putative kinase 1) and BNIP3 (Bcl-2 Interacting Protein 3), modulate mitochondrial apoptosis differently. If close links between the fission-inducing protein DRP1 and Bcl-2 family proteins, regulators of apoptosis, are demonstrated, the connection between mitophagy and apoptosis is still poorly understood. In Drosophila , we have shown that Rbf1, a homolog of the oncosuppressive protein pRb, induces cell death in proliferating larval tissues through a mechanism involving the interaction of Drp1 with Debcl, a pro-apoptotic protein of the Bcl-2 family. This interaction is necessary to induce mitochondrial fission, ROS production, and apoptosis. To better understand the interactions between the proteins involved in mitochondrial homeostasis and the apoptotic process, we focused on the role of two known players in mitophagy, the proteins PINK1 and BNIP3, during mitochondrial apoptosis induced by Rbf1 and Debcl in a proliferating Drosophila larval tissue. We show that Rbf1- or Debcl-induced apoptosis is accompanied by mitophagy. Interestingly, PINK1 and BNIP3 have distinct effects in regulating cell death. PINK1 promotes rbf1 - or debcl -induced apoptosis, whereas BNIP3 protects against Rbf1-induced apoptosis but reduces Debcl- induced tissue loss without inhibiting Debcl-induced cell death. Furthermore, our results indicate that BNIP3 is required to induce basal mitophagy while PINK1 is responsible for mitophagy induced by rbf1 overexpression. These results highlight the critical role of mitophagy regulators in controlling homeostasis and cell fate.