Study on the molecular mechanism of KPNA2 regulation of myocardial ischemia/delayed reperfusion injury through mitophagy.

Abstract

This study investigates the role of Karyopherin Subunit Alpha 2 (KPNA2) in myocardial ischemia/delayed reperfusion (I/dR) injury and its underlying molecular mechanisms. Using SD rat I/dR models and cell hypoxia/reoxygenation (H/R) models, we found that KPNA2 expression was significantly upregulated following I/dR treatment, leading to mitophagy dysfunction and myocardial cell damage. Mechanistic studies revealed that the transcription factor Paired box 6 (PAX6) promotes KPNA2 expression by binding to its promoter, while KPNA2 protein directly interacts with Phosphate Cytidylyltransferase 1 Alpha (PCYT1A). This KPNA2-PCYT1A interaction significantly inhibited mitophagy activity, as evidenced by the downregulation of key mitophagy molecules such as PINK1 and Parkin, along with a decreased LC3-II/LC3-I ratio and accumulation of p62 protein. In animal experiments, PAX6 inhibition downregulated KPNA2/PCYT1A expression, restored mitophagy function, alleviated myocardial injury, and improved cardiac function. This study, for the first time, elucidates a novel mechanism by which the PAX6-KPNA2-PCYT1A signaling axis regulates mitophagy in myocardial I/dR injury, providing potential targets for clinical treatment.