Mitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy is a result of diabetes-induced changes in the structure and function of the heart. Hyperglycemia affects multiple pathways in the diabetic heart, but excessive reactive oxygen species (ROS) generation and oxidative stress represent common denominators associated with adverse tissue remodeling. Indeed, key processes underlying cardiac remodeling in diabetes are redox sensitive, including inflammation, organelle dysfunction, alteration in ion homeostasis, cardiomyocyte hypertrophy, apoptosis, fibrosis, and contractile dysfunction. Extensive experimental evidence supports the involvement of mitochondrial ROS formation in the alterations characterizing the diabetic heart. In this review we will outline the central role of mitochondrial ROS and alterations in the redox status contributing to the development of diabetic cardiomyopathy. We will discuss the role of different sources of ROS involved in this process, with a specific emphasis on mitochondrial ROS producing enzymes within cardiomyocytes. Finally, the therapeutic potential of pharmacological inhibitors of ROS sources within the mitochondria will be discussed.

Keywords: diabetic cardiomyopathy; diabetic complication; mitochondria; oxidative stress; reactive oxygen species.

Figure 1

A schematic diagram depicting different factors involved in the onset and development of diabetic cardiomyopathy. AGEs, advanced glycation end products; ECM, extracellular matrix; ER, endoplasmic reticulum; FAO, fatty acid oxidation; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species.

Figure 2

Mitochondrial sources of ROS in diabetic cardiomyopathy. Diabetic milieu, characterized by hyperglycemia, hyperlipidemia, and inflammation, results in the up-regulation in the activity of mitochondrial ROS-producing enzymes. Superoxide can be produced by the respiratory chain through forward or reverse electron transport. In addition, calpain-1 translocates to the mitochondrial matrix in the diabetic heart and cleaves the α subunit of the ATP synthase, leading therefore to the reduction in its activity and mitochondrial dysfunction. On the other hand, in situations of stress, p66^Shc is phosphorylated and translocates to the IMS where it catalyzes the electron transfer from cytochrome c to oxygen (O₂) leading to the formation of hydrogen peroxide (H₂O₂). Finally, up-regulation of MAO activity upon exposure to high glucose and pro-inflammatory stimuli results in enhanced formation of H₂O₂ that can directly increase the susceptibility of mitochondria to undergo permeability transition. Post-translational modifications, such as oxidation or O-GlcNAcylation of respiratory chain complexes, can impair mitochondrial bioenergetics and function. All these events are implicated in the pathogenesis of diabetic cardiomyopathy by promoting mitochondrial and ER stress, leading to protein oxidation and Ca²⁺ homeostasis impairment, as well as sarcomere and ECM stiffness. AGEs, advanced glycation end products; ECM, extracellular matrix; ER, endoplasmic reticulum; FAO, fatty acid oxidation; IMM, inner mitochondrial membrane; IMS, intermembrane space; MAO, monoamine oxidase; MnSOD, manganese superoxide dismutase; OMM, outer mitochondrial membrane; O-GlcNAc, β-linked N-acetylglucosamine; ox, oxidation.