Alteration in mitochondrial Ca2 uptake disrupts insulin signaling in hypertrophic cardiomyocytesReport as inadecuate

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Cell Communication and Signaling

, 12:68

First Online: 07 November 2014Received: 30 April 2014Accepted: 14 October 2014


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 Ca 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 Ca signaling in normal and norepinephrine or insulin like growth factor-1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca-fluorescent probes we showed that insulin increases mitochondrial Ca levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca uniporter, as well as by siRNA-dependent mitochondrial Ca 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 Ca uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling.

ConclusionsMitochondrial Ca uptake is a key event in insulin signaling and metabolism in cardiomyocytes.

KeywordsInsulin Calcium Mitochondria Cardiac hypertrophy Inositol 1,4,5-triphosphate receptor Akt IGF-1 Catecholamines Electronic supplementary materialThe online version of this article doi:10.1186-s12964-014-0068-4 contains supplementary material, which is available to authorized users.

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Author: Tomás Gutiérrez - Valentina Parra - Rodrigo Troncoso - Christian Pennanen - Ariel Contreras-Ferrat - César Vasquez-Trinca


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