The ARVC-5-causing TMEM43 mutation disrupts lipid homeostasis and mitochondrial energy metabolism, leading to lipid droplet accumulation, mitochondrial degradation, and reduced lifespan.
A novel Drosophila model of ARVC-5 demonstrates that the TMEM43 mutation impairs lipid homeostasis and mitochondrial energy metabolism.
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Arrhythmogenic right ventricular cardiomyopathy type 5 is caused by the missense mutation S358L in the gene TMEM43 in humans. To date, the molecular mechanisms underlying the disease remain poorly understood. We established a CRISPR/Cas9 knock-in Drosophila model carrying the orthologous Tmem43p.S333L mutation to investigate these mechanisms in vivo. The resulting flies were viable but displayed reduced lifespan, smaller body size, lipid droplet accumulation, and mitochondrial defects. Proteomic and lipidomic profiling revealed a dosage-dependent misregulation of the energy metabolism, concomitant with reduced fatty acid synthesis and ß-oxidation rates, altered peroxisomal pathways, and changes in membrane phospholipid composition. Notably, phosphatidylethanolamine (PE) and phosphatidylinositol (PI) levels were elevated, while triacylglycerols were reduced. Ultrastructural analyses confirmed mitochondrial degradation in the muscle tissue of corresponding mutants. These findings establish Tmem43p.S333L knock-in flies as a robust in vivo model of ARVC-5, and support a role for TMEM43 in linking lipid homeostasis to mitochondrial energy metabolism and integrity. Mutation-derived impairments in these processes result in cardiomyopathy.
Jürgens et al. (Tue,) reported a other. The ARVC-5-causing TMEM43 mutation disrupts lipid homeostasis and mitochondrial energy metabolism, leading to lipid droplet accumulation, mitochondrial degradation, and reduced lifespan.
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