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 arrhyth...

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Autores principales:	Leroy C. Joseph, Michael V. Reyes, Edwin A. Homan, Blake Gowen, Uma Mahesh R. Avula, Chris N. Goulbourne, Elaine Y. Wan, John W. Elrod, John P. Morrow
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3583dde928184485acfbb8b933a21ddc
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spelling	oai:doaj.org-article:3583dde928184485acfbb8b933a21ddc2021-12-02T19:12:28ZThe mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet10.1038/s41598-021-97449-32045-2322https://doaj.org/article/3583dde928184485acfbb8b933a21ddc2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97449-3https://doaj.org/toc/2045-2322Abstract 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.Leroy C. JosephMichael V. ReyesEdwin A. HomanBlake GowenUma Mahesh R. AvulaChris N. GoulbourneElaine Y. WanJohn W. ElrodJohn P. MorrowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leroy C. Joseph Michael V. Reyes Edwin A. Homan Blake Gowen Uma Mahesh R. Avula Chris N. Goulbourne Elaine Y. Wan John W. Elrod John P. Morrow The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
description	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.
format	article
author	Leroy C. Joseph Michael V. Reyes Edwin A. Homan Blake Gowen Uma Mahesh R. Avula Chris N. Goulbourne Elaine Y. Wan John W. Elrod John P. Morrow
author_facet	Leroy C. Joseph Michael V. Reyes Edwin A. Homan Blake Gowen Uma Mahesh R. Avula Chris N. Goulbourne Elaine Y. Wan John W. Elrod John P. Morrow
author_sort	Leroy C. Joseph
title	The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
title_short	The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
title_full	The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
title_fullStr	The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
title_full_unstemmed	The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
title_sort	mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3583dde928184485acfbb8b933a21ddc
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The mitochondrial calcium uniporter promotes arrhythmias caused by high-fat diet

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