CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling

Abstract Prediabetic myocardium, induced by fructose-rich diet (FRD), is prone to increased sarcoplasmic reticulum (SR)-Ca2+ leak and arrhythmias due to increased activity of the Ca2+/calmodulin protein kinase II (CaMKII). However, little is known about the role of SR-mitochondria microdomains, mito...

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Autores principales:	Marilen Federico, Maite Zavala, Tamara Vico, Sofía López, Enrique Portiansky, Silvia Alvarez, Maria Celeste Villa Abrille, Julieta Palomeque
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a54e36dee0342b9aa851469f3efb5b0
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spelling	oai:doaj.org-article:8a54e36dee0342b9aa851469f3efb5b02021-12-02T19:16:14ZCaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling10.1038/s41598-021-99118-x2045-2322https://doaj.org/article/8a54e36dee0342b9aa851469f3efb5b02021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99118-xhttps://doaj.org/toc/2045-2322Abstract Prediabetic myocardium, induced by fructose-rich diet (FRD), is prone to increased sarcoplasmic reticulum (SR)-Ca2+ leak and arrhythmias due to increased activity of the Ca2+/calmodulin protein kinase II (CaMKII). However, little is known about the role of SR-mitochondria microdomains, mitochondrial structure, and mitochondrial metabolisms. To address this knowledge gap we measured SR-mitochondrial proximity, intracellular Ca2+, and mitochondrial metabolism in wild type (WT) and AC3-I transgenic mice, with myocardial-targeted CaMKII inhibition, fed with control diet (CD) or with FRD. Confocal images showed significantly increased spontaneous Ca2+ release events in FRD vs. CD WT cardiomyocytes. [3H]-Ryanodine binding assay revealed higher [3H]Ry binding in FRD than CD WT hearts. O2 consumption at State 4 and hydrogen peroxide (H2O2) production rate were increased, while respiratory control rate (RCR) and Ca2+ retention capacity (CRC) were decreased in FRD vs. CD WT isolated mitochondria. Transmission Electron Microscopy (TEM) images showed increased proximity at the SR-mitochondria microdomains, associated with increased tethering proteins, Mfn2, Grp75, and VDAC in FRD vs. CD WT. Mitochondria diameter was decrease and roundness and density were increased in FRD vs. CD WT specimens. The fission protein, Drp1 was significantly increased while the fusion protein, Opa1 was unchanged in FRD vs. CD WT hearts. These differences were prevented in AC3-I mice. We conclude that SR-mitochondria microdomains are subject to CaMKII-dependent remodeling, involving SR-Ca2+ leak and mitochondria fission, in prediabetic mice induced by FRD. We speculate that CaMKII hyperactivity induces SR-Ca2+ leak by RyR2 activation which in turn increases mitochondria Ca2+ content due to the enhanced SR-mitochondria tethering, decreasing CRC.Marilen FedericoMaite ZavalaTamara VicoSofía LópezEnrique PortianskySilvia AlvarezMaria Celeste Villa AbrilleJulieta PalomequeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marilen Federico Maite Zavala Tamara Vico Sofía López Enrique Portiansky Silvia Alvarez Maria Celeste Villa Abrille Julieta Palomeque CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
description	Abstract Prediabetic myocardium, induced by fructose-rich diet (FRD), is prone to increased sarcoplasmic reticulum (SR)-Ca2+ leak and arrhythmias due to increased activity of the Ca2+/calmodulin protein kinase II (CaMKII). However, little is known about the role of SR-mitochondria microdomains, mitochondrial structure, and mitochondrial metabolisms. To address this knowledge gap we measured SR-mitochondrial proximity, intracellular Ca2+, and mitochondrial metabolism in wild type (WT) and AC3-I transgenic mice, with myocardial-targeted CaMKII inhibition, fed with control diet (CD) or with FRD. Confocal images showed significantly increased spontaneous Ca2+ release events in FRD vs. CD WT cardiomyocytes. [3H]-Ryanodine binding assay revealed higher [3H]Ry binding in FRD than CD WT hearts. O2 consumption at State 4 and hydrogen peroxide (H2O2) production rate were increased, while respiratory control rate (RCR) and Ca2+ retention capacity (CRC) were decreased in FRD vs. CD WT isolated mitochondria. Transmission Electron Microscopy (TEM) images showed increased proximity at the SR-mitochondria microdomains, associated with increased tethering proteins, Mfn2, Grp75, and VDAC in FRD vs. CD WT. Mitochondria diameter was decrease and roundness and density were increased in FRD vs. CD WT specimens. The fission protein, Drp1 was significantly increased while the fusion protein, Opa1 was unchanged in FRD vs. CD WT hearts. These differences were prevented in AC3-I mice. We conclude that SR-mitochondria microdomains are subject to CaMKII-dependent remodeling, involving SR-Ca2+ leak and mitochondria fission, in prediabetic mice induced by FRD. We speculate that CaMKII hyperactivity induces SR-Ca2+ leak by RyR2 activation which in turn increases mitochondria Ca2+ content due to the enhanced SR-mitochondria tethering, decreasing CRC.
format	article
author	Marilen Federico Maite Zavala Tamara Vico Sofía López Enrique Portiansky Silvia Alvarez Maria Celeste Villa Abrille Julieta Palomeque
author_facet	Marilen Federico Maite Zavala Tamara Vico Sofía López Enrique Portiansky Silvia Alvarez Maria Celeste Villa Abrille Julieta Palomeque
author_sort	Marilen Federico
title	CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
title_short	CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
title_full	CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
title_fullStr	CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
title_full_unstemmed	CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
title_sort	camkii activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8a54e36dee0342b9aa851469f3efb5b0
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CaMKII activation in early diabetic hearts induces altered sarcoplasmic reticulum-mitochondria signaling

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