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

作者：Gutierrez Tomas; Parra Valentina; Troncoso Rodrigo; Pennanen Christian; Contreras Ferrat Ariel; Vasquez Trincado Cesar; Morales Pablo E; Lopez Crisosto Camila; Sotomayor Flores Cristian; Chiong Mario; Rothermel Beverly A; Lavandero Sergio^*

来源：Cell Communication and Signaling, 2014, 12(1): UNSP 68.

DOI：10.1186/s12964-014-0068-4

• Insulin
• Calcium
• Mitochondria
• Cardiac hypertrophy
• Inositol 1,4,5-triphosphate receptor
• Akt
• IGF-1
• Catecholamines

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. %26lt;br%26gt;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. %26lt;br%26gt;Conclusions: Mitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.

• 出版日期2014-11-7