The Role of Mitochondria in Metabolic Syndrome-Associated Cardiomyopathy

Abstract

With the rapid development of society, the incidence of metabolic syndrome (MS) is increasing rapidly. Evidence indicated that patients diagnosed with MS usually suffered from cardiomyopathy, called metabolic syndrome-associated cardiomyopathy (MSC). The clinical characteristics of MSC included cardiac hypertrophy and diastolic dysfunction, followed by heart failure. Despite many studies on this topic, the detailed mechanisms are not clear yet. As the center of cellular metabolism, mitochondria are crucial for maintaining heart function, while mitochondria dysfunction plays a vital role through mechanisms such as mitochondrial energy deprivation, calcium disorder, and ROS (reactive oxygen species) imbalance during the development of MSC. Accordingly, in this review, we will summarize the characteristics of MSC and especially focus on the mechanisms related to mitochondria. In addition, we will update new therapeutic strategies in this field.

Figure 1

The structural changes of MSC and the mitochondrial changes. Under physical condition, the cardiomyocytes generate energy about 40% via FA metabolism, and mitochondrial hemostasis is regulated via various mechanisms. Obesity, insulin resistance, diabetes, and dyslipidemia cause cardiomyopathy, characterized by thickness and stiffness of the ventricular wall (interstitial fibrosis and cardiomyocyte hypertrophy), cell death, and eventually contractile dysfunction. The accumulation of toxic metabolism intermediates and leads to decreased oxygen utilization induced by mitochondrial dysfunction (reactive oxygen species (ROS) generation, altered calcium, and ETC distribution).

Figure 2

Mitochondrial signaling in metabolic syndrome-related cardiomyopathy. (a) Dyslipidemia, insulin resistance, obesity, and hyperglycemia could cause cardiomyocytes altered calcium homeostasis, including the cytoplasmic calcium, SR, and mitochondrial calcium. Damaged mitochondria undergo fission and are finally cleaned by mitophagy. In addition, the damaged mitochondria exert mPTP opening and cytochrome c release, inducing apoptosis. (b) Dyslipidemia, insulin resistance, obesity, and hyperglycemia lead to lipotoxicity and accumulation of AGEs, leading to the activation of mitochondrial ROS-producing enzymes. p66Shc is activated and catalyzes the formation of hydrogen peroxide (H₂O₂). Increased ROS could disturb the mitochondrial oxidation respiratory chain, followed by cell death.