Activation of IRF3 impairs mitochondrial function and leads to heart failure. [CMI3OE vs Ctrl]
Averting heart failure in ischemic cardiomyopathy is challenging. Heightened inflammatory response and mitochondrial dysfunction drives the pathophysiology of heart failure. However, the transcriptional regulators within cardiomyocytes driving crosstalk between cardiac sterile inflammation and mitochondrial energy metabolism remain ill-defined. Here we identify elevated Ser396/Ser398 phosphorylation of the transcription factor IRF3, a key regulator of type I interferon (IFN) response, in the left ventricular of patients and mice with ischemic cardiomyopathy. Our data show that cardiomyocyte-specific Irf3 deficiency in mice attenuated contractile dysfunction upon myocardial infarction. Conversely, activation of Irf3 in cardiomyocytes through a phosphomimic Irf3 mutant repressed Pgc-1a expression leading to dysfunctional mitochondrial oxidative phosphorylation, impaired NAD metabolism and excessive type I IFN inflammatory milieu, collectively detrimental towards cardiac function. Restoring cardiomyocyte-specific Pgc-1a expression in Irf3-overexpressor mice attenuated the contractile dysfunction by augmenting metabolic flexibility towards fatty acid oxidation and decreasing inflammatory fibrotic responses. We identify Irf3 activation in cardiomyocytes as a potential in vivo model of type I IFN stimulated sterile inflammation that downregulates Pgc-1a and functions as a transcriptional nexus between inflammation and metabolic fuel switch contributing to heart failure. Overall design: To determine the downstream transcriptional changes by IRF3 activation in cardiomyocytes, we performed RNA-seq experiments and identified the transcriptional profile in the left ventricle upon cardiomyocyte-specific activation of IRF3 using IRF3-2D phosphomimic mutant transgene crossed to aMHCMCM.