Activation of IRF3 impairs mitochondrial function and leads to heart failure. [Rescue]

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: We identified the transcriptomic profile in the left ventricle of CMI3OE mice treated with AAV-PGC-1a or AAV-EGFP for 3 weeks followed by Tamoxifen induction of IRF3-2D gene expression.