1. Reduced reticulum-mitochondria Ca 2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy.
- Author
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Dia M, Gomez L, Thibault H, Tessier N, Leon C, Chouabe C, Ducreux S, Gallo-Bona N, Tubbs E, Bendridi N, Chanon S, Leray A, Belmudes L, Couté Y, Kurdi M, Ovize M, Rieusset J, and Paillard M
- Subjects
- Animals, Calcium Channels metabolism, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Type 2 complications, Diabetic Cardiomyopathies diet therapy, Diabetic Cardiomyopathies etiology, Diabetic Cardiomyopathies pathology, Diet, High-Fat, Dietary Sucrose, Endoplasmic Reticulum pathology, Energy Metabolism, Excitation Contraction Coupling, Inositol 1,4,5-Trisphosphate metabolism, Inositol 1,4,5-Trisphosphate Receptors metabolism, Insulin Resistance, Male, Mice, Inbred C57BL, Mitochondria, Heart pathology, Mitochondrial Proteins metabolism, Myocytes, Cardiac pathology, Voltage-Dependent Anion Channel 1 metabolism, Calcium metabolism, Calcium Signaling, Diabetic Cardiomyopathies metabolism, Endoplasmic Reticulum metabolism, Mitochondria, Heart metabolism, Myocytes, Cardiac metabolism
- Abstract
Type 2 diabetic cardiomyopathy features Ca
2+ 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.- Published
- 2020
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