What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function

Abstract: Diastolic dysfunction is common to both diabetic cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). Although commonly attributed to increased fibrosis, alterations in mitochondrial function and associated Ca 2+ handling may contribute to impaired cardiac function. With mitochondrial dysfunction, increased reactive oxygen species (ROS), inflammation, and decreased adenosine triphosphate/adenosine diphosphate ratio may lead to increased extracellular matrix and diminished contractile relaxation. In this article, we discuss recent research implicating deficient mitochondria-associated endoplasmic reticulum membranes (MAMs) as it relates to impaired metabolic function and what role that may have in diastolic dysfunction in diabetic cardiomyopathy. The contribution of mitochondrial dysfunction to diastolic dysfunction in HFpEF is less established, but equally credible based on preclinical studies. However, there are notable differences between diabetic cardiomyopathy and HFpEF. Recent evidence implicates impaired endoplasmic reticulum signaling, in particular the unfolded protein response (UPR), in the pathogenesis of HFpEF. With HFpEF, enhanced pressure on the mitochondrial “gas pedal” because of increased cytosolic Ca 2+ may perturb mitochondrial homeostasis. For diabetic cardiomyopathy and HFpEF, a better understanding of how altered cellular ion and redox status affect mitochondrial function is needed. Finally, we discuss the implications that mitochondrial dysfunction may have in devising novel therapeutic strategies for diabetic cardiomyopathy and HFpEF.