Altered reticulum-mitochondria interactions contribute to mitochondrial Ca2 + signaling dysfunction in the diabetic mice heart

• Published in: Archives of Cardiovascular Diseases Supplements Vol. 11; no. 2; p. 233
• Main Authors: Dia, M., Rieusset, J., Tubbs, E., Bendridi, N., Gomez, L., Ovize, M., Kurdi, M., Paillard, M.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.04.2019
• ISSN: 1878-6480
• DOI: 10.1016/j.acvdsp.2019.02.114

Diabetic cardiomyopathy has been linked to Ca2+signaling alterations, notably a decreased mitochondrial Ca2+uptake. Uncovering the changes occurring at Ca2+microdomains between reticulum and mitochondria in the heart has launched a new area of investigation for cardiometabolic diseases. We here aimed to study if the impairment of mitochondrial Ca2+ handling could be due to a dysregulation of the reticulum-mitochondria interactions or of the mitochondrial Ca2+ uniporter in the diabetic mice heart. Mice were either fed with a standard diet (SD: 16.9% proteins, 4.3% lipids) or a high-fat high sucrose diet (HFHSD: 20% proteins, 36% lipids) for 16 weeks. Cardiac mitochondria associated membranes (MAM) composition was analyzed by proteomics and immunoblotting. Proximity ligation assay, calcium imaging and hypoxia/reoxygenation were performed on isolated cardiomyocytes. Our HFHSD mice displayed a cardiac insulin resistance and hypertrophy. Decreased MAM/pure mitochondria content in the HFHSD vs SD heart was observed, with an elevated level of proteins involved in lipid metabolism and a decrease in tethering proteins. Decreased IP3R-VDAC proximity upon HFHSD was concomitant to a reduced IP3R-stimulated Ca2+ transfer to mitochondria, with no changes in mitochondrial calcium uniporter protein expression and function. Additionally, decreased amplitude of cytosolic Ca2+ transients was seen in the HFHSD cardiomyocytes, with no significant changes in the reticular Ca2+ release level. Besides, increased cell death susceptibility was measured after both in vitro hypoxia/reoxygenation and in vivo ischemia/reperfusion under HFHSD. Our data, therefore, indicate that decreased reticulum-mitochondria interactions trigger an impaired mitochondrial Ca2+ handling in the diabetic mice heart, with no alteration of the mitochondrial Ca2+ uniporter, while the enhanced susceptibility to cell death could be referred to lipid toxicity.