Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy

BECLIN 1 is a central player in macroautophagy. AMBRA1, a BECLIN 1-interacting protein, positively regulates the BECLIN 1-dependent programme of Autophagy. In this study, we show that AMBRA1 binds preferentially the mitochondrial pool of the antiapoptotic factor Bcl-2, and that this interaction is disrupted following Autophagy induction. Further, AMBRA1 can compete with both mitochondrial and endoplasmic reticulum-resident Bcl-2 (mito-BCL-2 and ER-BCL-2, respectively) to bind BECLIN 1. Moreover, after Autophagy induction, AMBRA1 is recruited to BECLIN 1. Altogether, these results indicate that, in normal conditions, a pool of AMBRA1 binds preferentially mito-BCL-2; after Autophagy induction, AMBRA1 is released from Bcl-2, consistent with its ability to promote BECLIN 1 activity. In addition, we found that the binding between AMBRA1 and mito-BCL-2 is reduced during Apoptosis. Thus, a dynamic interaction exists between AMBRA1 and Bcl-2 at the mitochondria that could regulate both BECLIN 1-dependent Autophagy and Apoptosis.