Natriuretic peptides increase cGMP around cardiomyocyte mitochondria and protect against apoptosis

Natriuretic peptides (NPs) increase cGMP, show beneficial cardiovascular effects and regulate energy metabolism in other tissues. However, little is known about their direct effect on cardiac mitochondria and cardiomyocyte apoptosis. Here, we examined whether NPs increase cGMP around mitochondria and alter apoptosis in cardiomyocytes. We constructed a novel FRET-based biosensor with high selectivity towards cGMP and found that ANP and CNP increase cGMP at the outer mitochondrial membrane. Moreover, ANP and CNP increased phosphorylation of the pro-apoptotic protein Drp1 and CNP prevented fragmentation of mitochondria. Stimulating cardiomyocytes with ANP or CNP reduced apoptosis, caspase 9 activation and cytochrome c release, suggesting that NPs decrease apoptosis through the intrinsic pathway that involves mitochondria. We suggest that cGMP increase in the outer mitochondrial membrane microdomain that inhibits the pro-apoptotic protein Drp1, leading to reduced mitochondrial fragmentation and thereby reduced apoptosis.