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Updated: Aug 20, 2025

Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy
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BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia

Yun-Ling He1, Jian Li2,3, Sheng-Hui Gong1

  • 1Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.

Cell Death & Disease
|November 17, 2022
PubMed

Insights

Hypoxia triggers mitophagy by activating the JNK1/2-BNIP3 pathway, which enhances the binding of BNIP3 to LC3 and prevents its degradation. Protein phosphatase 1/2A reverses this process, highlighting a key mechanism for cellular adaptation to low oxygen.

Area of Science:

  • Cellular Biology
  • Molecular Mechanisms
  • Metabolic Regulation

Background:

  • Mitophagy is a crucial process for maintaining mitochondrial health by removing damaged mitochondria.
  • BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3) acts as a mitophagy receptor, particularly under hypoxic stress.
  • The precise regulation of BNIP3-mediated mitophagy during hypoxia remains incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing BNIP3 regulation and mitophagy induction under hypoxic conditions.
  • To identify key signaling pathways and protein interactions involved in hypoxia-induced mitophagy.

Main Methods:

  • Investigated the phosphorylation status of BNIP3 in response to hypoxia.
  • Utilized biochemical assays to assess protein-protein interactions between BNIP3 and LC3 (microtubule-associated protein 1 light chain 3).
  • Examined the role of JNK1/2 (c-Jun N-terminal kinase 1/2) and PP1/2A (protein phosphatase 1/2A) in regulating BNIP3 stability and mitophagy.

Main Results:

  • Hypoxia induces JNK1/2-mediated phosphorylation of BNIP3 at Ser60/Thr66, stabilizing BNIP3 against proteasomal degradation.
  • Phosphorylated BNIP3 exhibits enhanced binding to LC3, promoting mitophagy.
  • PP1/2A dephosphorylates BNIP3, leading to its degradation and repression of mitophagy.

Conclusions:

  • The JNK1/2-BNIP3 signaling pathway is a critical regulator of mitophagy in response to hypoxia.
  • This pathway links mitochondrial quality control to cellular adaptation under low oxygen conditions.
  • The JNK1/2-BNIP3 pathway represents a potential therapeutic target for diseases associated with hypoxia.

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