Mitochondrial Mechanisms in Diabetic Cardiomyopathy

Abstract

Mitochondrial medicine is increasingly discussed as a promising therapeutic approach, given that mitochondrial defects are thought to contribute to many prevalent diseases and their complications. In individuals with diabetes mellitus (DM), defects in mitochondrial structure and function occur in many organs throughout the body, contributing both to the pathogenesis of DM and complications of DM. Diabetic cardiomyopathy (DbCM) is increasingly recognized as an underlying cause of increased heart failure in DM, and several mitochondrial mechanisms have been proposed to contribute to the development of DbCM. Well established mechanisms include myocardial energy depletion due to impaired adenosine triphosphate (ATP) synthesis and mitochondrial uncoupling, and increased mitochondrial oxidative stress. A variety of upstream mechanisms of impaired ATP regeneration and increased mitochondrial reactive oxygen species have been proposed, and recent studies now also suggest alterations in mitochondrial dynamics and autophagy, impaired mitochondrial Ca²⁺ uptake, decreased cardiac adiponectin action, increased O-GlcNAcylation, and impaired activity of sirtuins to contribute to mitochondrial defects in DbCM, among others. In the current review, we present and discuss the evidence that underlies both established and recently proposed mechanisms that are thought to contribute to mitochondrial dysfunction in DbCM.

Keywords: Diabetes mellitus; Diabetic cardiomyopathies; Heart failure; Mitochondria.

Fig. 1. Proposed mechanisms of mitochondrial dysfunction in diabetic cardiomyopathy. Defects in the electron transport chain (ETC), increased monoamine oxidases (MAO) activity and decreased antioxidative capacity lead to increased reactive oxygen species/reactive nitrogen species (ROS/RNS) generation and subsequent oxidative damage. Posttranslational mechanisms like altered protein O-linked beta-N-acetylglucosamine glycosylation (O-GlcNAcylation) and increased protein acylation due to impaired SIRT activity, as well as mitochondrial proteome remodeling, impaired peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) signaling and miRNA dysregulation contribute to impaired ETC activity, ultimately leading to energy depletion and oxidative stress. Increased fatty acid oxidation (FAO) and/or impaired adiponectin (ADN)/adiponectin receptor 1 (AdipoR1) signaling may contribute to mitochondrial uncoupling and decreased cardiac efficiency. Increased mitochondrial fission, decreased mitophagy and altered mitochondrial biogenesis contribute to mitochondrial ROS and energy depletion and are interrelated mechanisms that may modulate each other. Impaired mitochondrial calcium uniporter (MCU) activity decreases mitochondrial Ca²⁺ uptake and thereby impairs activity of Ca²⁺-dependent dehydrogenases and oxidative phosphorylation. PINK1, phosphatase and tensin homolog-induced putative kinase 1; Drp1, dynamin-related protein 1; Opa1, optic atrophy 1; Mfn2, mitofusion 2; AMPK, adenosine monophosphate-activated protein kinase; SIRT1, sirtuin 1; AoC, antioxidative capacity; ATP, adenosine triphosphate.