Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes

Cell Communication and Signaling

Research

Cristian Sotomayor-Flores¹  Christian Pennanen¹  César Vasquez-Trincado¹  Pablo E Morales¹  Camila Lopez-Crisosto¹  Tomás Gutiérrez¹  Mario Chiong²  Valentina Parra³  Sergio Lavandero⁴  Ariel Contreras-Ferrat⁵  Rodrigo Troncoso⁶  Beverly A Rothermel⁷ 

[1] Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Centro de Estudios Moleculares de la Célula, Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, 75390-8573, Dallas, TX, USA;Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, 75390-8573, Dallas, TX, USA;Centro de Estudios Moleculares de la Célula, Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Institute for Research in Dental Science, Faculty of Dentistry, Universidad de Chile, 838049, Santiago, Chile;Advanced Center for Chronic Disease (ACCDiS), Facultad de Ciencias Quimicas y Farmaceuticas & Facultad de Medicina, Universidad de Chile, 838049, Santiago, Chile;Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, 7830490, Santiago, Chile;Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, 75390-8573, Dallas, TX, USA;

关键词: Insulin;    Calcium;    Mitochondria;    Cardiac hypertrophy;    Inositol 1,4,5-triphosphate receptor;    Akt;    IGF-1;    Catecholamines;   

DOI  :  10.1186/s12964-014-0068-4

 received in 2014-04-30, accepted in 2014-10-14,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundCardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood.ResultsIn the present study we investigated insulin-dependent mitochondrial Ca2+ signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca2+-fluorescent probes we showed that insulin increases mitochondrial Ca2+ levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca2+ uniporter, as well as by siRNA-dependent mitochondrial Ca2+ uniporter knockdown. Norepinephrine-stimulated cardiomyocytes showed a significant decrease in endoplasmic reticulum-mitochondrial contacts compared to either control or insulin like growth factor-1-stimulated cells. This resulted in a reduction in mitochondrial Ca2+ uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca2+ uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling.ConclusionsMitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.

【 授权许可】

Unknown   
© Gutierrez et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.