Reduced reticulum\u2013mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

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

doi:10.1007/s00395-020-00835-7

Abstract

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.

Highlights

With the current alarming progression of type 2 diabetes (T2D), diabetic cardiomyopathy (DCM) is nowadays recognized as a major cardiovascular complication with a four-to-fivefold increase in the risk of heart failure for diabetic patients [26, 28]
16 weeks of high-fat high-sucrose diet (HFHSD) led to a cardiac insulin resistance and to an early phenotype of diabetic cardiomyopathy
Our study demonstrates that the alteration of the mitochondria-associated membranes (MAM) thickness towards tighter interactions not compatible with the Ca2+ transport process is an early trigger of the mitochondrial dysfunctions during diabetic cardiomyopathy

Summary

Introduction

With the current alarming progression of type 2 diabetes (T2D), diabetic cardiomyopathy (DCM) is nowadays recognized as a major cardiovascular complication with a four-to-fivefold increase in the risk of heart failure for diabetic patients [26, 28]. Hyperglycemia, insulin resistance, and hyperinsulinemia result in cardiac hypertrophy and fibrosis that alter diastolic function [5, 24, 25]. The excitation–contraction coupling and the mitochondriadependent energy-supply balance, which require finetuned calcium (Ca2+) dynamics, are potential contributors of DCM progression [4, 20, 24]. A reduced mitochondrial C a2+ uptake [16,. Mitochondrial Ca2+ mishandling can be considered as a key player of cardiomyocyte dysfunction in DCM. The precise mechanisms behind the disruption of mitochondrial Ca2+ homeostasis during DCM progression remain poorly known

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Discussion

Conclusion