Phosphorylation dependent mitochondrial translocation of Nr4a3 provokes cardiomyocyte death

Abstract Immediate early gene-nuclear receptor subfamily 4, group A, member 3 (Nr4a3) is implicated in a variety of cellular processes. However, its role and underlying mechanisms in ischemia reperfusion (IR) remain unknown. Here, we show that Nr4a3 expression is upregulated in the heart after IR and that cardiac specific Nr4a3 deficiency protects against myocardial ischemic injury and improves cardiac function. The overexpression of Nr4a3 in both neonatal and adult mouse hearts is sufficient to cause left ventricular dilation and contractile dysfunction without additional ischemic stress. Mechanistically, ischemia or hypoxia triggers Nr4a3 phosphorylation and translocation from the nucleus to mitochondria, where it interacts with and promotes Bnip3 integration into the mitochondrial membrane. This integration leads to mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial permeability transition pore (ΔΨm), which causes cardiomyocyte apoptotic and necrotic death. Our findings describe an Nr4a3-Bnip3 mitochondrial pathway underlying cell death.