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bioRxiv · 10.1101/2020.08.27.271270

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

He, Y.-L.·Gong, S.-H.·Cheng, X.·Zhao, M.·Zhao, T.·Zhao, Y.·Fan, M.·Zhu, L.-L.·Wu, L.-Y.
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Abstract

Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3, 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 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, while PP1/2A 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.

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He, Y.-L., Gong, S.-H., Cheng, X., Zhao, M., Zhao, T., Zhao, Y., Fan, M., Zhu, L.-L., Wu, L.-Y.. 2020-08-28. BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia. https://doi.org/10.1101/2020.08.27.271270

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