Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy

Tania Zaglia, Paola Ceriotti, Antonio Campo, Giulia Borile, Andrea Armani, Pierluigi Carullo, Valentina Prando, Raffaele Coppini, Vladimiro Vida, Tomas O. Stølen, Wisløff Ulrik, Elisabetta Cerbai, Giovanni Stellin, Giuseppe Faggian, Diego De Stefani, Marco Sandri, Rosario Rizzuto, Fabio Di Lisa, Tullio Pozzan, Daniele Catalucci & 1 others Marco Mongillo

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The mitochondrial Ca2+uniporter complex (MCUC) is a multimeric ion channel which, by tuning Ca2+ influx into the mitochondrial matrix, finely regulates metabolic energy production. In the heart, this dynamic control of mitochondrial Ca2+ uptake is fundamental for cardiomyocytes to adapt to either physiologic or pathologic stresses. Mitochondrial calcium uniporter (MCU), which is the core channel subunit of MCUC, has been shown to play a critical role in the response to β-adrenoreceptor stimulation occurring during acute exercise. The molecular mechanisms underlying the regulation of MCU, in conditions requiring chronic increase in energy production, such as physiologic or pathologic cardiac growth, remain elusive. Here, we show that microRNA-1 (miR-1), a member of the muscle-specific microRNA (myomiR) family, is responsible for direct and selective targeting of MCU and inhibition of its translation, thereby affecting the capacity of the mitochondrial Ca2+uptake machinery. Consistent with the role of miR-1 in heart development and cardiomyocyte hypertrophic remodeling, we additionally found that MCU levels are inversely related with the myomiR content, in murine and, remarkably, human hearts from both physiologic (i.e., postnatal development and exercise) and pathologic (i.e., pressure overload) myocardial hypertrophy. Interestingly, the persistent activation of ß-adrenoreceptors is likely one of the upstream repressors of miR-1 as treatment with β-blockers in pressure-overloaded mouse hearts prevented its down-regulation and the consequent increase in MCU content. Altogether, these findings identify the miR-1/MCU axis as a factor in the dynamic adaptation of cardiac cells to hypertrophy.

Original languageEnglish
Pages (from-to)E9006-E9015
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
DOIs
Publication statusPublished - Oct 24 2017

Fingerprint

MicroRNAs
Cardiac Myocytes
Hypertrophy
Mitochondrial Dynamics
Pressure
Ion Channels
mitochondrial calcium uniporter
Down-Regulation
Exercise
Muscles
Growth

Keywords

  • Cardiomyocyte calcium
  • Heart
  • MicroRNA
  • Mitochondrial calcium uniporter
  • Myocardial hypertrophy

ASJC Scopus subject areas

  • General

Cite this

Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. / Zaglia, Tania; Ceriotti, Paola; Campo, Antonio; Borile, Giulia; Armani, Andrea; Carullo, Pierluigi; Prando, Valentina; Coppini, Raffaele; Vida, Vladimiro; Stølen, Tomas O.; Ulrik, Wisløff; Cerbai, Elisabetta; Stellin, Giovanni; Faggian, Giuseppe; De Stefani, Diego; Sandri, Marco; Rizzuto, Rosario; Di Lisa, Fabio; Pozzan, Tullio; Catalucci, Daniele; Mongillo, Marco.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 43, 24.10.2017, p. E9006-E9015.

Research output: Contribution to journalArticle

Zaglia, T, Ceriotti, P, Campo, A, Borile, G, Armani, A, Carullo, P, Prando, V, Coppini, R, Vida, V, Stølen, TO, Ulrik, W, Cerbai, E, Stellin, G, Faggian, G, De Stefani, D, Sandri, M, Rizzuto, R, Di Lisa, F, Pozzan, T, Catalucci, D & Mongillo, M 2017, 'Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 43, pp. E9006-E9015. https://doi.org/10.1073/pnas.1708772114
Zaglia, Tania ; Ceriotti, Paola ; Campo, Antonio ; Borile, Giulia ; Armani, Andrea ; Carullo, Pierluigi ; Prando, Valentina ; Coppini, Raffaele ; Vida, Vladimiro ; Stølen, Tomas O. ; Ulrik, Wisløff ; Cerbai, Elisabetta ; Stellin, Giovanni ; Faggian, Giuseppe ; De Stefani, Diego ; Sandri, Marco ; Rizzuto, Rosario ; Di Lisa, Fabio ; Pozzan, Tullio ; Catalucci, Daniele ; Mongillo, Marco. / Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 43. pp. E9006-E9015.
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AU - Zaglia, Tania

AU - Ceriotti, Paola

AU - Campo, Antonio

AU - Borile, Giulia

AU - Armani, Andrea

AU - Carullo, Pierluigi

AU - Prando, Valentina

AU - Coppini, Raffaele

AU - Vida, Vladimiro

AU - Stølen, Tomas O.

AU - Ulrik, Wisløff

AU - Cerbai, Elisabetta

AU - Stellin, Giovanni

AU - Faggian, Giuseppe

AU - De Stefani, Diego

AU - Sandri, Marco

AU - Rizzuto, Rosario

AU - Di Lisa, Fabio

AU - Pozzan, Tullio

AU - Catalucci, Daniele

AU - Mongillo, Marco

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N2 - The mitochondrial Ca2+uniporter complex (MCUC) is a multimeric ion channel which, by tuning Ca2+ influx into the mitochondrial matrix, finely regulates metabolic energy production. In the heart, this dynamic control of mitochondrial Ca2+ uptake is fundamental for cardiomyocytes to adapt to either physiologic or pathologic stresses. Mitochondrial calcium uniporter (MCU), which is the core channel subunit of MCUC, has been shown to play a critical role in the response to β-adrenoreceptor stimulation occurring during acute exercise. The molecular mechanisms underlying the regulation of MCU, in conditions requiring chronic increase in energy production, such as physiologic or pathologic cardiac growth, remain elusive. Here, we show that microRNA-1 (miR-1), a member of the muscle-specific microRNA (myomiR) family, is responsible for direct and selective targeting of MCU and inhibition of its translation, thereby affecting the capacity of the mitochondrial Ca2+uptake machinery. Consistent with the role of miR-1 in heart development and cardiomyocyte hypertrophic remodeling, we additionally found that MCU levels are inversely related with the myomiR content, in murine and, remarkably, human hearts from both physiologic (i.e., postnatal development and exercise) and pathologic (i.e., pressure overload) myocardial hypertrophy. Interestingly, the persistent activation of ß-adrenoreceptors is likely one of the upstream repressors of miR-1 as treatment with β-blockers in pressure-overloaded mouse hearts prevented its down-regulation and the consequent increase in MCU content. Altogether, these findings identify the miR-1/MCU axis as a factor in the dynamic adaptation of cardiac cells to hypertrophy.

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KW - Myocardial hypertrophy

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