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BNIP3-mediated mitophagy attenuates hypoxic–ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62–KEAP1–NRF2 pathway activation to maintain iron and redox homeostasis

Acta Pharmacologica Sinica volume 46, pages 33–51 (2025)Cite this article

Abstract

As a major contributor to neonatal death and neurological sequelae, hypoxic-ischemic encephalopathy (HIE) lacks a viable medication for treatment. Oxidative stress induced by hypoxic-ischemic brain damage (HIBD) predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature. Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model. Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery, followed by exposure to hypoxia for 2 h. The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide (0.5, 1 mg/kg, i.p.) 1 h before hypoxia, or in combination with mitochondrial division inhibitor-1 (Mdivi-1, 20 mg/kg, i.p.), and ferroptosis inhibitor Ferrostatin-1 (Fer-1) (2 mg/kg, i.p.) at the end of the hypoxia period. The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC12 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion. We showed that HIBD induced mitochondrial damage, ROS overproduction, intracellular iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by the pretreatment with Tat-SPK2 peptide, and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown. Ferroptosis inhibitors Fer-1 and deferoxamine B (DFO) reversed the accumulation of iron and lipid peroxides caused by Mdivi-1, hence reducing ferroptosis triggered by HI. We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway. BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway, which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1, HO-1, and DHODH/FSP1-CoQ10-NADH. This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE.

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Fig. 1: Mitophagy is activated after hypoxic-ischemic brain damage (HIBD) in neonatal rats.
Fig. 2: The mitophagy activator Tat-SPK2 peptide significantly attenuated HIBD in neonatal rats by activating BNIP3-mediated mitophagy.
Fig. 3: BNIP3-mediated mitophagy confers resistance to ferroptosis in neonatal rats HIBD.
Fig. 4: The Tat-SPK2 peptide, an activator of mitophagy, improves mitochondrial dysfunction in OGD/R.
Fig. 5: The Tat-SPK2 peptide, an activator of mitophagy, significantly attenuates HIBD-induced accumulation of iron ions and lipid peroxides and ferroptosis.
Fig. 6: BNIP3 silencing worsens OGD/R-induced lipid peroxidation and ferroptosis, which are rescued by Fer-1 or DFO.
Fig. 7: BNIP3-mediated mitophagy inhibits neuronal ferroptosis via a GPX4-independent pathway.
Fig. 8: BNIP3-mediated mitophagy upregulates the P62-KEAP1-NRF2 pathway to activate NRF2 contributing to ferroptosis resistance.
Fig. 9: Blockade of NRF2 abolished the protective effect of mitophagy in oxidative stress-induced ferroptosis.
Fig. 10: Schematic representation of mitophagy, ROS, iron metabolism and ferroptosis in HIBD.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82301957 and No.82001382), the National Natural Science Foundation of China (No.82271405 and No.82071379), the China Postdoctoral Science Foundation (No. 2022M712311), and Suzhou Science and Technology Development Program (Healthcare Science and Technology Innovation Project) (No. SKY2022177).

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  1. These authors contributed equally: Xin-xin Wang, Mei Li, Xiao-wen Xu

Authors and Affiliations

  1. Department of Brain Research, Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, 215025, China

    Xin-xin Wang, Mei Li, Xiao-wen Xu, Yi-ming Jin, Li-li Li & Hong Ni

  2. Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Pharmaceutical Science, Suzhou, 199 Ren Ai Road, Suzhou, 215123, China

    Wen-bin Zhao, Zheng-hong Qin & Rui Sheng

  3. Institute of Heath Technology, Global Institute of Software Technology, Qingshan Road, Suzhou Science & Technology Tower, Hi-Tech Area, Suzhou, 215163, China

    Zheng-hong Qin

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Contributions

HN and RS conceived and supervised the study. XXW and ML designed research, XXW, ML, XWX, WBZ and YMJ carried out the experiments. XXW, ML and XWX collected, analyzed and interpreted the data. XXW wrote the manuscript. ML, XWX, WBZ, YMJ, LLL, ZHQ, RS and HN revised the manuscript. LLL, ZHQ, RS and HN contributed reagents/materials/analysis tools. XXW, ML and LLL provided funding support. All authors read and approved the submitted manuscript. We thank Bronwen Gardner, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn/), for editing the English text of a draft of this manuscript.

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Correspondence to Rui Sheng or Hong Ni.

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Wang, Xx., Li, M., Xu, Xw. et al. BNIP3-mediated mitophagy attenuates hypoxic–ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62–KEAP1–NRF2 pathway activation to maintain iron and redox homeostasis. Acta Pharmacol Sin 46, 33–51 (2025). https://doi.org/10.1038/s41401-024-01365-x

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