GSK3β-mediated phosphorylation of IF1 at Ser27 destabilizes mitochondrial ATP synthase inhibitory factor 1 to aggravate cardiac ischemia/reperfusion injury.

Authors

Beiduo Tian, Yao Dong, Chenlu Yuan, Huimin Su, Zihan Li, Mingxuan Hong, Shichun Shen, Shuchou Xia, Jiawei Wu

Published in

International immunopharmacology. Volume 187. Pages 117253. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

Myocardial ischemia-reperfusion (I/R) injury is a major cause of ischemic cardiomyopathy and chronic heart failure, underscoring the need for new cardioprotective strategies. ATP synthase inhibitory factor 1 (IF1) maintains mitochondrial function and limits oxidative damage during I/R injury. Our previous work showed that IF1 protects the heart through AMPK activation; however, IF1 protein levels decline sharply during I/R despite stable mRNA expression, suggesting post-translational regulation. This study aimed to elucidate the molecular mechanism underlying IF1 instability and to characterize a newly identified phosphorylation site at serine 27 (S27).
Mass spectrometric analysis of HEK293 cells overexpressing human IF1 identified a novel phosphorylation site at serine 27 (S27), and subsequent experiments validated that phosphorylation at this specific site was markedly induced during the I/R process. The functional role of IF1 was further investigated in an IF1-KO mouse model of myocardial I/R, comparing the effects of wild-type IF1 (WT) and a non-phosphorylatable IF1 mutant (S27A).
Mass spectrometric analysis revealed S27 as a novel phosphorylation site of IF1 that is markedly induced during I/R injury. This phosphorylation promoted the interaction between IF1 and the E3 ubiquitin ligase NEDD4, enhancing IF1 ubiquitination and proteasomal degradation. In vivo, restoration of IF1-either WT or S27A-attenuated acute and chronic myocardial injury, preserved mitochondrial integrity, and improved cardiac function. Notably, the S27A mutant, resistant to phosphorylation-dependent degradation, provided superior cardioprotection compared with WT IF1.
Glycogen Synthase Kinase-3 beta (GSK3β) mediated phosphorylation of IF1 at the newly identified S27 site destabilizes IF1 via the ubiquitin-proteasome pathway, contributing to myocardial I/R injury. Blocking this modification stabilizes IF1 and enhances cardioprotection. These findings reveal a previously unrecognized mechanism of IF1 regulation and identify S27 phosphorylation as a promising therapeutic target against reperfusion-induced cardiac damage.

PMID:
42574807
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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