Moderate downregulation of NDUFA13 promotes cardiomyocytes proliferation and heart regeneration through the glycolysis/c‑Myc/Ccnd1 axis

The poor prognosis of heart diseases is largely attributable to the limited proliferative capacity of cardiomyocytes. Cardiomyocyte proliferation and heart regeneration has garnered increasing attention, with a focus on the identification of novel therapeutic targets. In the present study, NADH dehydrogenase ubiquinone I α subcomplex 13 (NDUFA13), a subunit protein of mitochondria complex I, was found to serve an important role during this regenerative period of cardiomyocytes. Both in vitro and in vivo, moderate downregulation of NDUFA13 promoted cardiomyocytes proliferation, increased expression of cell cycle genes, reduced fibrosis and thus benefitted heart regeneration after apical resection. In addition, downregulation of NDUFA13 not only preserved mitochondrial function but also enhanced glycolysis, which is a metabolic shift that is important for modulating the state of cardiomyocytes. Using western blot and reverse transcription‑quantitative PCR, NDUFA13 expression was analyzed at different growth stages in mice and identified its association with cardiomyocyte proliferation. To investigate the role of NDUFA13 in vitro, a moderately NDUFA13‑downregulated cell model was developed using siRNA; in vivo, Myh6‑cre^ERT Ndufa13^flox/+ mice were generated and performed apical resection surgery. Through proliferation markers, echocardiography and fibrotic staining, the relationship between NDUFA13 and heart regeneration was revealed. To investigate the functional mechanisms, oxidative phosphorylation and glycolytic activity in NDUFA13‑downregulated primary cardiomyocytes was assessed. Upon confirming the changes in glycolytic flux, the expression of c‑Myc and key cell cycle‑related genes was measured. Chromatin immunoprecipitation experiments further revealed c‑Myc binding to the promoter region of Ccnd1. Increasing levels of glycolysis upregulated the expression of c‑Myc, which could bind to the promotor zone of cell cycle gene cyclin D1, thus promoting cardiomyocytes proliferation. Through mitochondrial‑nuclear communication, signals originating from the mitochondria are converted into nuclear transcriptional responses, which in turn drive cellular proliferation. Therefore, the present study demonstrated the key role of NDUFA13 in cardiac regeneration and its potential as a target for heart injury treatment.