MYCN is an essential regulator of cardiomyocyte proliferation and mitochondrial function. AHA Conference Repository

American Heart Association

Final ID: Mon122

MYCN is an essential regulator of cardiomyocyte proliferation and mitochondrial function.

Abstract Body: Adult cardiomyocytes (CMs) have a limited capacity for regeneration following cardiac injury; therefore, intense interest has focused on the definition of the molecular factors that promote CM proliferation. We defined the transcription factor MYCN, as a key regulator of CM proliferation during the neonatal period. We previously reported that the conditional deletion (cKO) of Mycn in neonatal CMs completely abolished cell cycle activity, resulting in the complete absence of cardiac regeneration following a LAD ligation-induced injury compared to control hearts. To decipher the cellular and molecular mechanisms of MYCN, we performed single-nuclei multiomics of P4 control and Mycn cKO hearts. The Mycn cKO hearts showed a marked decrease in the cluster of proliferating CMs, accompanied by significant downregulation of cell-cycle regulators in all CMs. Furthermore, our studies revealed extensive perturbations in gene expression that regulated glycolysis, fatty acid oxidation, and the electron transport chain. Bioinformatic scoring of control and Mycn cKO metabolic gene expression predicted a significant reduction in glycolysis. To examine the mechanisms whereby MYCN regulates CM mitochondrial activity, we performed Seahorse mitochondrial stress and fatty acid stress assays on neonatal primary CMs. Decreased mitochondrial respiration was observed following Mycn ablation, whereas Mycn overexpression led to enhanced mitochondrial respiration. In addition to the changes in respiration, mitochondrial architecture was altered and reflected Mycn levels. Mitotracker staining revealed a globular, fragmented phenotype to the mitochondria of Mycn cKO CMs. Quantification of mitochondrial architecture showed a significant decrease in roots and branch points compared to control mitochondria. These results provide new mechanistic insights regarding MYCN-mediated regulation of CM metabolism and proliferation. Furthermore, these mechanistic insights provide a platform for therapeutic interventions and cardiac repair and regeneration following injury.

Leonard, Riley ( University of Minnesota , Minneapolis , Minnesota , United States )
Das, Satyabrata ( University of Minnesota , Minneapolis , Minnesota , United States )
Li, Qinglu ( University of Minnesota , Minneapolis , Minnesota , United States )
Hailemariam, Kidus ( University of Minnesota , Minneapolis , Minnesota , United States )
Zhang, Jianyi ( University of Alabama at Birmingham , Birmingham , Alabama , United States )
Garry, Mary ( University of Minnesota , Minneapolis , Minnesota , United States )
Garry, Daniel ( LILLEHEI HEART INSTITUTE - U OF MN , Minneapolis , Minnesota , United States )

Author Disclosures:

Meeting Info:

Basic Cardiovascular Sciences 2026

2026

Boston, Massachusetts

Session Info:

Poster Session 1

Monday, 07/13/2026 , 04:30PM - 07:00PM

Poster Session and Reception

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