Newfoundland Mutation <i>TMEM43</i> -p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction

BACKGROUND: -p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5. METHODS: for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs. RESULTS: -p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes. CONCLUSIONS: -p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.