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

Aug 23, 2024Acta pharmacologica Sinica

BNIP3 helps protect newborn rat brains from oxygen and blood flow loss by reducing iron-related cell damage through activating the p62-KEAP1-NRF2 pathway to keep iron and oxidative balance

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Abstract

Hypoxic-ischemic brain damage significantly increases ferroptosis in neonatal rats, which may be mitigated by mitophagy activation using the Tat-SPK2 peptide.

Neonatal rats subjected to hypoxic-ischemic brain damage exhibited mitochondrial damage, increased reactive oxygen species, iron accumulation, and lipid peroxidation.
Pretreatment with the mitophagy activator Tat-SPK2 peptide significantly reduced markers of ferroptosis in neonatal rats.
Inhibition of mitophagy through Mdivi-1 treatment or BNIP3 knockdown worsened ferroptosis and associated cellular damage.
Ferroptosis inhibitors, such as Ferrostatin-1 and deferoxamine B, counteracted the effects of mitochondrial division inhibition, reducing iron and lipid peroxide accumulation.
BNIP3-mediated mitophagy was shown to maintain iron and redox balance via the P62-KEAP1-NRF2 pathway, independent of the GPX4-GSH pathway.

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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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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

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