Loss of STMP1 Perturbs Mitochondrial Cristae and Drives Cellular Inflammation and Heart Failure

BACKGROUND: Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP guanosine monophosphate–AMP adenosine monophosphate synthase)–STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood. METHODS: We investigated the function of STMP1 (short transmembrane mitochondrial protein 1), a 47–amino acid nuclear-encoded mitochondrial-localized peptide featuring a distinctive GxxxGxxxG glycine zipper domain. A mouse with cardiomyocyte-specific knockout of Stmp1 ( Stmp1 -KO) was generated to investigate its role in cardiac function. We profiled the transcriptome, proteome, and metabolome of Stmp1 -KO hearts to determine its functional mechanism of action. Electron microscopy was used to assess the impact of STMP1 depletion and functional rescue after adeno-associated virus 9–mediated gene restoration in the Stmp1 -KO mouse. RESULTS: STMP1 is downregulated specifically in cardiomyocytes, and not other cardiac cell types, in aged mice and humans. Genetic loss of Stmp1 in cardiomyocytes resulted in heart failure in vivo. STMP1 interacts with components of the cristae organizing complexes MICOS (mitochondrial contact site and cristae organizing complex) and SAM (sorting and assembly machinery). Consequent to Stmp1 loss, mitochondrial cristae were destabilized, mitochondrial DNA was mislocalized to the cytosol, and the cGAS–STING pathway was activated, with ensuing cellular inflammation and cardiomyocyte cell death. Restoration of wild-type Stmp1 or STING inhibition significantly rescued cardiac function in vivo. CONCLUSION: Our work reveals a mechanism connecting the micropeptide STMP1 to mitochondrial cristae architecture and cardiomyocyte cellular inflammation, both of which are present as potential drivers of heart failure and cardiac aging.