maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Loss of the paired-like homeodomain transcription factor 2 () in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in conditional-knockout ( CKO) mice. We found adipose-like tissue in CKO hearts 60 days after MI induced surgically at postnatal day 2 but not at day 8. Molecular and cellular analyses showed the onset of adipogenic signaling in mutant hearts after MI. Lineage tracing experiments showed a non-cardiomyocyte origin of the adipose-like tissue. Interestingly, we found that promotes mitochondrial function through its gene regulatory network, and that the knockdown of a key mitochondrial target gene, , also leads to the accumulation of myocardial fat tissue. Single-nuclei RNA-seq revealed that -deficient hearts were oxidatively stressed. Our findings reveal a role for in maintaining proper cardiac cellular composition during heart regeneration via the maintenance of proper mitochondrial structure and function.