Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway

Christian Pennanen, Valentina Parra, Camila López-Crisosto, Pablo E. Morales, Andrea del Campo, Tomás Gutierrez, Pablo Rivera-Mejías, Jovan Kuzmicic, Mario Chiong, Antonio Zorzano, Beverly A. Rothermel, Sergio Lavandero

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72 Scopus citations

Abstract

Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through a1-adrenergic receptors to increase cytoplasmic Ca2+, activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling.

Original languageEnglish (US)
Pages (from-to)2659-2671
Number of pages13
JournalJournal of cell science
Volume127
Issue number12
DOIs
StatePublished - 2014

Keywords

  • Calcineurin
  • Cardiac hypertrophy
  • Drp1
  • Metabolism
  • Mitochondrial fission
  • Norepinephrine

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    Pennanen, C., Parra, V., López-Crisosto, C., Morales, P. E., del Campo, A., Gutierrez, T., Rivera-Mejías, P., Kuzmicic, J., Chiong, M., Zorzano, A., Rothermel, B. A., & Lavandero, S. (2014). Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. Journal of cell science, 127(12), 2659-2671. https://doi.org/10.1242/jcs.139394