Cardiovascular diseases associated with metabolic syndrome remain frequent and still disabling for patients. The uncovering of Ca²⁺ microdomains between mitochondria and reticulum (SR) in the heart has launched a new area of investigation for cardiometabolic diseases.

Here, we sought to determine the structural and functional role of the SR-mitochondria interactions in the mice heart during diabetes. We hypothesized that an alteration of the SR-mitochondria interactions would impair the Ca²⁺ signaling between the two organelles, thus leading to contractile dysfunction.

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. In the HFHSD group, half of the mice were subjected to metformin gavage, an antidiabetic agent, for the last 4 weeks.

Cardiac mitochondria associated membranes (MAM) isolation showed an increased protein amount of MAM/pure mitochondria in the HFHSD group vs. SD mice, which was prevented by metformin treatment (SD: 2.0±0.4, HFHSD: 5.5±0.9, HFHSD+MET: 2.8±0.4, n=5). After 70min hypoxia-2hrs reoxygenation, HFHSD isolated cardiomyocytes displayed higher propidium-iodide positive cells compared to SD and HFHSD+MET groups (60±1 vs. SD: 46±3 and HFHSD+MET: 50±2%, n=5). Interestingly, histamine-stimulated Ca²⁺ transfer to mitochondria was reduced by 50% in HFHSD±MET cardiomyocytes. Concomitantly, IP3R-VDAC interactions assessed by proximity ligation assay were 30–40% reduced in HFHSD±MET cardiomyocytes.

Hence, our data indicate a role for the SR-mitochondria interactions during diabetes in the heart in hypoxia-reoxygenation-induced cell death and in the Ca²⁺ signaling dysfunction. Indeed, reduced formation of the IP3R-VDAC Ca²⁺ channeling complex and of the IP3R-stimulated Ca²⁺ transfer to mitochondria in the HFHSD±MET cardiomyocytes suggest an inappropriate thickness of the extended MAM (too close or too far) for the IP3R complex formation.