BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia

Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3), a mitochondrial outer membrane protein, is a Mitophagy receptor that mediates Mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate Mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 (c-Jun N-terminal kinase 1/2) phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives Mitophagy by facilitating the direct binding of BNIP3 to LC3 (microtubule-associated protein 1 light chain 3), while PP1/2A (protein Phosphatase 1/2A) represses Mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate Mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links Mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.