A Heterozygous Mitochondrial Gene Variant Sensitizes Cardiomyocytes to Cytokine Stress and amplifies Proinflammatory Chemokine Signaling in Inflammatory Cardiomyopathy

Cells were exposed to IFN-γ alone or in combination with tumor necrosis factor-α and evaluated using mitochondrial functional assays and integrated proteomic, transcriptomic, and metabolomic profiling. DHODH R135C cardiomyocytes exhibited baseline mitochondrial stress that was amplified by cytokine exposure, including impaired bioenergetics, oxidative stress, mitochondrial fragmentation, and suppression of mitochondrial homeostatic pathways.

These changes were accompanied by cytoplasmic double-stranded DNA accumulation and partially cGAS-dependent amplification of CXCL10 and interferon-stimulated-gene expression. Patient-derived R135C cardiomyocytes reproduced the principal mitochondrial abnormalities, which were rescued by isogenic correction. Increased CXCL10, CXCL9, and CXCR3 expression in CCC myocardium supported in vivo relevance.

These findings identify DHODH R135C as a latent mitochondrial vulnerability unmasked by inflammatory cytokines and suggest a feed-forward interaction between cardiomyocyte dysfunction and IFN-γ-producing immune cells. This GEO Series contains the bulk RNA-sequencing data generated from the AC16 and patient-derived cardiomyocyte models.