N6-methyladenosine reader IGF2BP2 regulates NIPSNAP1-mediated mitophagy and mitochondrial dynamics to alleviate hepatic ischemia-reperfusion injury

Abstract

Background: Hepatic ischemia-reperfusion (I/R) injury related to liver transplantation and hepatic resection remains a challenge in clinical practice. Accumulating evidence indicates that mitochondrial dysfunction is a critical cause of I/R injury. The protein 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) is involved in the regulation of mitophagy and the recruitment of autophagy receptor proteins independent of PTEN induced putative kinase 1.

Aim: To clarify the protective mechanism of NIPSNAP1 against hepatic I/R, with a focus on mitophagy and mitochondrial dynamics, as well as the potential mechanism by which n6-methyladenosine (m6A) modification regulates NIPSNAP1.

Methods: Mice were administered an adeno-associated virus in vivo and a hepatic I/R model was established via portal vein interruption followed by reperfusion to explore the effect of NIPSNAP1 on hepatic I/R. HepG2 cells were subjected to hypoxia/reoxygenation treatment in vitro.

Results: We observed a significant downregulation of both NIPSNAP1 and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) expression in vivo and in vitro. NIPSNAP1 knockdown impaired mitophagy and disrupted mitochondrial dynamics; in contrast, NIPSNAP1 overexpression resulted in the opposite effects. Further studies revealed that IGF2BP2 functions as an m6A reader that targets and binds NIPSNAP1, thereby regulating its mRNA stability.

Conclusion: NIPSNAP1 prevents hepatic I/R injury by promoting mitophagy and maintaining mitochondrial homeostasis, serving as a novel target of the m6A reader IGF2BP2. Therefore, targeting the IGF2BP2/NIPSNAP1 axis may facilitate the development of better therapeutics for hepatic I/R.

Keywords: 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1; Hepatic ischemia-reperfusion; Interacted with insulin-like growing factor 2; Mitochondrial dynamics; Mitophagy; mRNA stability; mRNA-binding protein 2.