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

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.

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Publication Details

Journal
Nature Communications
Published
2026-02-27
DOI
https://doi.org/10.1038/s41467-026-69792-4
Primary Topic
Cardiac Fibrosis and Remodeling
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Jöerg Heeren, Glynis Klinke, Luisa Lange, Roberto Carlos Frias-Soler et al.
Nature Communications
Cardiac Fibrosis and Remodeling
article

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

Jöerg Heeren, Glynis Klinke, Luisa Lange, Roberto Carlos Frias-Soler, Ioannis Evangelakos, Anushka Deshpande, Carolin Lerchenmüller, Ashraf Yusuf Rangrez, Ludger Scheja, Viacheslav O. Nikolaev, Marc Freichel, Almut Schulze, Nesrin Schmiedel, Manju Kumari, Evan D. Rosen, Nicolàs Palacio-Escat, Thomas Eschenhagen, Kirstie A. De Jong, Adriano de Britto Chaves-Filho, Marceline M. Fuh, Michael Berlin, Norbert Frey, Tian Tian, Jakob Johannes Buss
article en

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.

Nature CommunicationsVol. 17(1)
Broad Institute (US), Beth Israel Deaconess Medical Center (US), Universität Hamburg (DE), German Cancer Research Center (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), University Hospital of Zurich (CH), University Medical Center Hamburg-Eppendorf (DE), German Centre for Cardiovascular Research (DE), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, National Institutes of Health
Openalex Percentile: Top 46%
Cardiac Fibrosis and Remodeling
DOIOpen Access PDFOpenAlex
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