Altered reticulum-mitochondria interactions contribute to mitochondrial Ca2 + signaling dysfunction in the diabetic mice heart
2019
Introduction
Diabetic cardiomyopathyhas been linked to Ca2 + signaling alterations, notably a decreased mitochondrial Ca2 + uptake. Uncovering the changes occurring at Ca2 + microdomains between
reticulumand mitochondria in the heart has launched a new area of investigation for cardiometabolic diseases. Objective 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 +
uniporterin the diabetic mice heart. Methods 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 imagingand hypoxia/reoxygenation were performed on isolated cardiomyocytes. Results 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 uniporterprotein 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. Conclusion 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.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
0
References
0
Citations
NaN
KQI