MTFP1 loss sensitizes to mtDNA-driven sterile inflammation and heart failure in mice

Abstract

Mitochondrial integrity is paramount to heart homeostasis. Under certain stress conditions, mitochondrial DNA (mtDNA) can leak into the cytosol and trigger type I innate immunity via the DNA sensing cGAS-STING pathway, the downstream interferon (IFN) regulatory factor 3 (IRF3) and cell surface receptor IFNAR1. Our previous work shows that loss of the inner membrane (IM) protein Mitochondrial Fission Process 1 (MTFP1) in cardiomyocytes of mice (cMKO) disturbs mitochondrial IM integrity leading to the activation of immune responses and a progressive dilated cardiomyopathy (DCM), which culminates into heart failure (HF) and middle-aged death. Investigate the impact of MTFP1 loss on mtDNA driven type I immune response and inflammation. In vitro, Mtfp1-/- mouse embryonic fibroblasts (MEFs) depleted or not of mtDNA, Sting or Irf3 were subjected to mitochondrial outer membrane permeabilization to assess the Interferons Stimulated Genes (ISGs) expression and IRF3 phosphorylation. In vivo, cMKO mice were additionally deleted of Sting or Ifnar1 and subjected to echocardiography to assess DCM progression. Upon treatment, Mtfp1-/- MEFs display increased ISGs expression and IRF3 phosphorylation compared to WT cells, which is abrogated by the depletion of mtDNA, STING or IRF3 in these cells. In vivo, whole body deletion of STING in cMKO mice mitigates HF, whereas IFNAR1 ablation fully rescues cardiac dysfunction and remodeling and extends lifespan of mice. Collectively, our data suggest a role of MTFP1 in restraining mtDNA-dependent inflammation, which in vivo fosters HF in the cMKO mice.