The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet

Abstract

Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (Mcu), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.

CaMKII as a Therapeutic Target in Cardiovascular Disease

“…CaMKII-dependent SR Ca 2+ leak is linked to mitochondrial metabolic dysfunction, presumably due to changes in Ca 2+ retention capacity of the mitochondria ( 99 ). Inhibition of extramitochondrial CaMKII protects cardiac mitochondria from Ca 2+ overload, loss of inner membrane potential, increased ROS, and resulting arrhythmia in models of prediabetes or obesity ( 99 , 100 ). CaMKII is also found in mitochondrial fractions ( 34 ) and has been shown to have direct effects on mitochondrial metabolism ( 33 ).…”

Regular Exercise in Drosophila Prevents Age-Related Cardiac Dysfunction Caused by High Fat and Heart-Specific Knockdown of skd

“…HFD can reduce Kv1.5, which generates repolarizing currents. Abnormal repolarization appears to play a role in the pathophysiology of arrhythmias after HFD [ 72 ]. In addition, high lipids exacerbate lipid accumulation and alter the cardiac structure and environment, and we showed that HFD altered Drosophila heart structure, HR, HP, DI, and SI.…”

Implications of MCU complex in metabolic diseases

“…CaMKII determines mitochondrial stress responses in heart 137 . Excitingly, in studies targeting high‐fat‐mediated arrhythmias, MCU knockout mice on a high‐fat diet did not exhibit activation of CaMKII compared to controls 78 . And this MCU knockout‐mediated CAMKII inhibition protects cardiomyocytes from saturated fatty acid‐induced mitochondrial dysfunction and exempts ventricular tachycardia after a high‐fat diet 78 .…”

“…Excitingly, in studies targeting high‐fat‐mediated arrhythmias, MCU knockout mice on a high‐fat diet did not exhibit activation of CaMKII compared to controls 78 . And this MCU knockout‐mediated CAMKII inhibition protects cardiomyocytes from saturated fatty acid‐induced mitochondrial dysfunction and exempts ventricular tachycardia after a high‐fat diet 78 . Although evidence suggests that MCU‐mediated mitochondrial Ca 2+ homeostasis plays a role in metabolic heart disease, unfortunately, we do not yet fully understand the mechanism, and the relationship between MCU and the development of cardiometabolic disorders would be a valuable research direction in the future.…”