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Review
. 2024 Jul 18;23(1):261.
doi: 10.1186/s12933-024-02357-1.

Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction

Michael W Rudokas  1 , Margaret McKay  1   2 , Zeren Toksoy  1 , Julia N Eisen  1 , Markus Bögner  1 , Lawrence H Young  1 , Fadi G Akar  3   4   5
Affiliations
Review

Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction

Michael W Rudokas et al. Cardiovasc Diabetol. .

Abstract

Mitochondria play a central role in cellular energy metabolism, and their dysfunction is increasingly recognized as a critical factor in the pathogenesis of diabetes-related cardiac pathophysiology, including vulnerability to ischemic events that culminate in myocardial infarction on the one hand and ventricular arrhythmias on the other. In diabetes, hyperglycemia and altered metabolic substrates lead to excessive production of reactive oxygen species (ROS) by mitochondria, initiating a cascade of oxidative stress that damages mitochondrial DNA, proteins, and lipids. This mitochondrial injury compromises the efficiency of oxidative phosphorylation, leading to impaired ATP production. The resulting energy deficit and oxidative damage contribute to functional abnormalities in cardiac cells, placing the heart at an increased risk of electromechanical dysfunction and irreversible cell death in response to ischemic insults. While cardiac mitochondria are often considered to be relatively autonomous entities in their capacity to produce energy and ROS, their highly dynamic nature within an elaborate network of closely-coupled organelles that occupies 30-40% of the cardiomyocyte volume is fundamental to their ability to exert intricate regulation over global cardiac function. In this article, we review evidence linking the dynamic properties of the mitochondrial network to overall cardiac function and its response to injury. We then highlight select studies linking mitochondrial ultrastructural alterations driven by changes in mitochondrial fission, fusion and mitophagy in promoting cardiac ischemic injury to the diabetic heart.

Keywords: Arrhythmia; Diabetes; Ischemia; Ischemia-reperfusion injury; Mitochondria; Mitochondrial dynamics; ROS (reactive oxygen species); ROS-induced ROS-release.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic illustrating the functional and physical features of mitochondrial network dynamics. The processes of biogenesis, fusion, fission and mitophagy dictate the morphology, density and ultrastructure of the mitochondrial network within the cardiomyocyte, which in turn affect the functional coupling/synchronization of individual mitochondria. An increase in mitochondrial production can lead to rapid amplification of ROS across the mitochondrial network via activation of ROS-sensitive mitochondrial channels. A hierarchal activation pattern of ROS sensitive channels causes early activation of TSPO/IMAC leading to reversible mitochondrial membrane potential oscillations that drive electrophysiological instability via cyclical activation of sarcolemmal ATP-sensitive K channels. This promotes conduction abnormalities and arrhythmias. On the other hand, higher levels of oxidative stress can activate the mPTP to cause irreversible mitochondrial depolarization leading to cell necrosis and myocardial infarction, a major risk factor for malignant arrhythmias and sudden cardiac death
Fig. 2
Fig. 2
Schematic illustrating the multi-scale process by which individual mitochondria can lead to organ level arrythmias. Diabetes causes an increase in ROS production and impairment in ROS scavenging. ROS levels are amplified through an autocatalytic feed-forward process of ROS-induced ROS-release which culminates in metabolic oscillations and rapid mitochondrial uncoupling. This causes activation of ATP-sensitive potassium channels resulting in membrane inexcitability at the cellular level and a phenomenon termed metabolic sink that leads to conduction block at the tissue level. Heterogeneous formation of these metabolic sinks results in ventricular arrhythmias
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