Ucp2 regulates neonatal cardiomyocytes proliferation through modulation of their mitochondrial metabolism

Abstract

A major block to mammalian cardiac regeneration is the limited capacity of adult cardiomyocytes (CMs) to proliferate in response to injury. CMs proliferation is linked to oxidative metabolism: at birth, neonatal CMs endure a metabolic switch, with high reliance on fatty acid oxidation. This leads to increased mtROS production that has been shown to mediate their cell-cycle arrest. Thus, studying mitochondrial activity in the neonate is critical to understand constrains on CMs proliferation, regardless of their age. In this context, we focus of Ucp2, a mitochondrial carrier that plays a key role in regulation of cell fuel preferences and mtROS production. Our goal is to investigate whether Ucp2 can regulate neonatal CMs proliferation through modulation of their oxidative metabolism. Using inducible and complete Ucp2 KOs mice models together with RNAseq, flow cytometry and Seahorse analysis, we have addressed the role of Ucp2 in regulation of neonatal CMs proliferation, mtROS levels, mitochondrial biogenesis and metabolic activity. Being expressed at low levels during development, Ucp2 is upregulated from P1 to P7. Its expression then decreases to become barely detectable in the adult, thus correlating with CMs proliferative period. We show that neonatal Ucp2-/- CMs display a reduced mitochondrial respiration (OCR) that is not compensated by glycolysis. This low OCR is accompanied by a strong decrease in mitochondrial mass, together with alterations of ETC complexes expression, and to an increased reliance on glutaminolysis. In addition to decreased ATP/ADP ratio, we show that this impaired metabolic activity leads to reduction of CMs proliferation, a phenotype that is mediated by p38MAPK signaling pathway. We are currently assessing the consequences of loss of Ucp2 on neonatal heart metabolites levels and mitochondrial network. We hypothesize that Ucp2, through the export of metabolites from mitochondria to cytosol, takes part in mitochondrial retrograde signaling leading to regulation of CMs maturation and proliferation.