MRG15 orchestrates glycolysis and the pentose phosphate pathway to facilitate heart regeneration following myocardial infarction

ABSTRACT: Metabolic reprogramming is crucial for adult heart regeneration after myocardial infarction (MI). Here, we identify the MORF4-related gene on chromosome 15 (MRG15) as a key orchestrator of cardiomyocyte metabolism to drive cardiomyocyte proliferation. MRG15 expression is upregulated in both hypoxic cardiomyocytes and infarcted human and mouse hearts. Cardiomyocyte-specific Mrg15 overexpression enhances glycolysis and the pentose phosphate pathway (PPP), promoting cardiomyocyte proliferation and cardiac function restoration after MI, whereas Mrg15 deficiency impairs heart regeneration. Mechanistically, cytoplasmic MRG15 interacts with hexokinase 2 (HK2) and enhances its protein stability by preventing its chaperone-mediated autophagy (CMA)-dependent degradation, which requires MRG15 residues 141–145. MRG15-mediated stabilization of HK2 orchestrates glycolysis and PPP, thereby facilitating cardiomyocyte proliferation and heart regeneration in adult mice post-MI. Our results underscore the importance of MRG15-mediated metabolic reprogramming in heart regeneration. By fine-tuning the activity of glycolysis and PPP, MRG15 represents a compelling therapeutic target for regenerative interventions following ischemic injury.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS15770 | MetaboLights | 2026-09-22

REPOSITORIES: MetaboLights