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

Cell Death Dis. 2022 Nov 17;13(11):966. doi: 10.1038/s41419-022-05418-z.

Yun-Ling He ^# ¹, Jian Li ^# ² ³, Sheng-Hui Gong ¹, Xiang Cheng ¹, Ming Zhao ¹, Yan Cao ², Tong Zhao ¹, Yong-Qi Zhao ¹, Ming Fan ⁴ ⁵ ⁶ ⁷, Hai-Tao Wu ⁸ ⁹, Ling-Ling Zhu ¹⁰ ¹¹, Li-Ying Wu ¹² ¹³

Affiliations

1 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
2 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
3 Beijing Institute of Microbiology and Epidemiology, Beijing, 100850, China.
4 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. [email protected].
5 Chinese Institute for Brain Research, Beijing, 102206, China. [email protected].
6 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. [email protected].
7 Lanzhou University School of Information Science & Engineering, Lanzhou, 730000, China. [email protected].
8 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. [email protected].
9 Chinese Institute for Brain Research, Beijing, 102206, China. [email protected].
10 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. [email protected].
11 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. [email protected].
12 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. [email protected].
13 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850, China. [email protected].
# Contributed equally.

PMID: 36396625 DOI: 10.1038/s41419-022-05418-z

Abstract

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.

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