Reduced reticulum-mitochondria Ca 2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

• Published in: Basic research in cardiology 2020-11, Vol.115 (6), p.74
• Main Authors: Dia, Maya, Gomez, Ludovic, Thibault, Helene, Tessier, Nolwenn, Leon, Christelle, Chouabe, Christophe, Ducreux, Sylvie, Gallo-Bona, Noelle, Tubbs, Emily, Bendridi, Nadia, Chanon, Stephanie, Leray, Aymeric, Belmudes, Lucid, Couté, Yohann, Kurdi, Mazen, Ovize, Michel, Rieusset, Jennifer, Paillard, Melanie
• Format: Article
• Language: English
• ISSN: 1435-1803

Type 2 diabetic cardiomyopathy features Ca signaling abnormalities, notably an altered mitochondrial Ca handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca homeostasis, the reticulum-mitochondrial Ca coupling, and/or the mitochondrial Ca entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum-mitochondria interface revealed tighter interactions not compatible with Ca transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca sensors were performed to measure Ca fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R-VDAC interaction and a reduced IP3-stimulated Ca transfer to mitochondria, with no changes in reticular Ca level, cytosolic Ca transients, and mitochondrial Ca uniporter function. Disruption of organelle Ca exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.