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

Gutiérrez T.; Parra, V; Troncoso R.; Pennanen C.; Contreras-Ferrat, A; Vasquez-Trincado, C; Morales PE; López-Crisosto, C; Sotomayor-Flores, C; Chiong M.; Rothermel BA; Lavandero S.

Keywords: insulin, calcium, mitochondria, catecholamines, igf-1, akt, cardiac hypertrophy, Inositol 1,4,5-triphosphate receptor

Abstract

Background: Cardiac 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. Results: In 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. Conclusions: Mitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.

Más información

Título según WOS: Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes
Título según SCOPUS: Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes
Título de la Revista: CELL COMMUNICATION AND SIGNALING
Volumen: 12
Número: 1
Editorial: BMC
Fecha de publicación: 2014
Idioma: English
DOI:

10.1186/s12964-014-0068-4

Notas: ISI, SCOPUS