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

Tomás Gutiérrez, Valentina Parra, Rodrigo Troncoso, Christian Pennanen, Ariel Contreras-Ferrat, César Vasquez-Trincado, Pablo E. Morales, Camila Lopez-Crisosto, Cristian Sotomayor-Flores, Mario Chiong, Beverly A. Rothermel, Sergio Lavandero

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number68
JournalCell Communication and Signaling
Volume12
Issue number1
DOIs
StatePublished - Nov 7 2014

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Cardiac Myocytes
Insulin
Norepinephrine
Somatomedins
Endoplasmic Reticulum
Metabolism
Inositol 1,4,5-Trisphosphate Receptors
Glucose
Cardiomegaly
Glycolysis
Mitochondria
Fluorescent Dyes
Oxygen Consumption
Hypertrophy
Energy Metabolism
Small Interfering RNA
Insulin Resistance
Pharmacology
Chemical activation
Oxygen

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gutiérrez, T., Parra, V., Troncoso, R., Pennanen, C., Contreras-Ferrat, A., Vasquez-Trincado, CÃ., ... Lavandero, S. (2014). Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes. Cell Communication and Signaling, 12(1), [68]. https://doi.org/10.1186/s12964-014-0068-4

Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes. / Gutiérrez, Tomás; Parra, Valentina; Troncoso, Rodrigo; Pennanen, Christian; Contreras-Ferrat, Ariel; Vasquez-Trincado, César; Morales, Pablo E.; Lopez-Crisosto, Camila; Sotomayor-Flores, Cristian; Chiong, Mario; Rothermel, Beverly A.; Lavandero, Sergio.

In: Cell Communication and Signaling, Vol. 12, No. 1, 68, 07.11.2014.

Research output: Contribution to journalArticle

Gutiérrez, T, Parra, V, Troncoso, R, Pennanen, C, Contreras-Ferrat, A, Vasquez-Trincado, CÃ, Morales, PE, Lopez-Crisosto, C, Sotomayor-Flores, C, Chiong, M, Rothermel, BA & Lavandero, S 2014, 'Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes', Cell Communication and Signaling, vol. 12, no. 1, 68. https://doi.org/10.1186/s12964-014-0068-4
Gutiérrez T, Parra V, Troncoso R, Pennanen C, Contreras-Ferrat A, Vasquez-Trincado Cà et al. Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes. Cell Communication and Signaling. 2014 Nov 7;12(1). 68. https://doi.org/10.1186/s12964-014-0068-4
Gutiérrez, Tomás ; Parra, Valentina ; Troncoso, Rodrigo ; Pennanen, Christian ; Contreras-Ferrat, Ariel ; Vasquez-Trincado, César ; Morales, Pablo E. ; Lopez-Crisosto, Camila ; Sotomayor-Flores, Cristian ; Chiong, Mario ; Rothermel, Beverly A. ; Lavandero, Sergio. / Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes. In: Cell Communication and Signaling. 2014 ; Vol. 12, No. 1.
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AU - Troncoso, Rodrigo

AU - Pennanen, Christian

AU - Contreras-Ferrat, Ariel

AU - Vasquez-Trincado, César

AU - Morales, Pablo E.

AU - Lopez-Crisosto, Camila

AU - Sotomayor-Flores, Cristian

AU - Chiong, Mario

AU - Rothermel, Beverly A.

AU - Lavandero, Sergio

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N2 - 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.

AB - 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.

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