Reduced reticulum–mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

Maya Dia (1) , Ludovic Gomez (1) , Helene Thibault (1) , Nolwenn Tessier (1) , Christelle Leon (1) , Christophe Chouabe (1) , Sylvie Ducreux (1) , Noelle Gallo-Bona (1) , Emily Tubbs (1) , Nadia Bendridi (1) , Stéphanie Chanon (1) , Aymeric Leray (2) , Lucid Belmudes (3) , Yohann Couté (3) , Mazen Kurdi (4) , Michel Ovize (1) , Jennifer Rieusset (1) , Melanie Paillard (1)

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
2 ICB - Laboratoire Interdisciplinaire Carnot de Bourgogne
3 EDyP - Etude de la dynamique des protéomes
4 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]

Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum-mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ 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 Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ 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 Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ 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, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum-mitochondria Ca2+ 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 Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.

Mots clés: Diabetic cardiomyopathy; Ca2+ flux; Metabolic syndrome disease; Protein database; Mitochondria-associated membranes MAM; Proteomic analysis of cardiac MAM proteome

Domaines: Cardiologie et système cardiovasculaire; Endocrinologie et métabolisme

Maya Dia, Ludovic Gomez, Helene Thibault, Nolwenn Tessier, Christelle Leon, et al.. Reduced reticulum–mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy. Basic Research in Cardiology, 2020, 115 (6), pp.74. ⟨10.1007/s00395-020-00835-7⟩. ⟨hal-03122630⟩