# Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure

## TL;DR

This study shows that IRF3 activation in heart muscle cells disrupts mitochondrial function and worsens heart failure by inhibiting PGC-1α.

## Contribution

The paper identifies IRF3 as a novel transcriptional regulator linking inflammation and metabolic dysfunction in heart failure.

## Key findings

- Elevated IRF3 phosphorylation is observed in patients and mice with ischemic cardiomyopathy.
- IRF3 activation represses Ppargc1α, leading to mitochondrial dysfunction and excessive IFN activation.
- Restoring Ppargc1α in IRF3-overexpressing mice improves cardiac function and reduces inflammation.

## Abstract

Heightened sterile inflammation and mitochondrial metabolic dysfunction drives the pathophysiology of heart failure in ischemic cardiomyopathy. Yet, the transcriptional regulators within cardiomyocytes driving crosstalk between inflammation and energy metabolism remain ill-defined. Here we identify elevated Ser396/Ser398 phosphorylation of the type I interferon (IFN) response regulating transcription factor IRF3 in the myocardium of patients and male mice with ischemic cardiomyopathy. Cardiomyocyte-specific IRF3 deficiency attenuates ischemia induced contractile dysfunction. Conversely, IRF3 activation in cardiomyocytes through a phosphomimetic IRF3 mutant represses Ppargc1α expression leading to dysfunctional mitochondrial oxidative phosphorylation, altered metabolic flux in the pentose phosphate pathway/TCA cycle, impaired NAD metabolism and an excessive type I IFN activation, collectively detrimental for cardiac function. Restoring cardiomyocyte-specific Ppargc1α expression in IRF3-overexpressor male mice attenuates contractile dysfunction by augmenting a metabolic shift towards fatty acid oxidation and decreasing inflammatory fibrotic responses. These findings identify IRF3 activation in cardiomyocytes as a transcriptional nexus between cardiac inflammation and metabolic fuel switch contributing to heart failure progression.

Transcriptional crosstalk between inflammation and energy metabolism within cardiomyocytes remains unclear. Here, the authors identify IRF3/PGC-1α as a bidirectional transcriptional nexus between IFN response and mitochondrial oxidative phosphorylation in cardiomyocytes altering cardiac function.