期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 43, 页码 E9006-E9015出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1708772114
关键词
microRNA; mitochondrial calcium uniporter; heart; myocardial hypertrophy; cardiomyocyte calcium
资金
- European Community Seventh Framework Program [HEALTH-F2-2009-241526]
- EUTrigTreat
- Telethon-Italy [GGP11224]
- Italian Ministry of University and Research Fondo per gli Investimenti della Ricerca di Base (FIRB)-Futuro in Ricerca [RBFR12I3KA]
- Fondazione Cariparo Mitochondrial Ca2+ uptake and cardiac pathophysiology
- European Union (European Research Council mitoCalcium) [294777]
- European Research Council (ERC) [294777] Funding Source: European Research Council (ERC)
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 beta-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 beta-adrenoreceptors is likely one of the upstream repressors of miR-1 as treatment with beta-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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