Resumen
Rationale: The regulator of calcineurin 1 (RCAN1) inhibits CN (calcineurin), a Ca2+-activated protein phosphatase important in cardiac remodeling. In humans, RCAN1 is located on chromosome 21 in proximity to the Down syndrome critical region. The hearts and brains of Rcan1 KO mice are more susceptible to damage from ischemia/ reperfusion (I/R); however, the underlying cause is not known. Objective: Mitochondria are key mediators of I/R damage. The goal of these studies was to determine the impact of RCAN1 on mitochondrial dynamics and function. Methods and Results: Using both neonatal and isolated adult cardiomyocytes, we show that, when RCAN1 is depleted, the mitochondrial network is more fragmented because of increased CN-dependent activation of the fission protein, DRP1 (dynamin-1-like). Mitochondria in RCAN1-depleted cardiomyocytes have reduced membrane potential, O2 consumption, and generation of reactive oxygen species, as well as a reduced capacity for mitochondrial Ca2+ uptake. RCAN1-depleted cardiomyocytes were more sensitive to I/R; however, pharmacological inhibition of CN, DRP1, or CAPN (calpains; Ca2+-activated proteases) restored protection, suggesting that in the absence of RCAN1, CAPN-mediated damage after I/R is greater because of a decrease in the capacity of mitochondria to buffer cytoplasmic Ca2+. Increasing RCAN1 levels by adenoviral infection was sufficient to enhance fusion and confer protection from I/R. To examine the impact of more modest, and biologically relevant, increases in RCAN1, we compared the mitochondrial network in induced pluripotent stem cells derived from individuals with Down syndrome to that of isogenic, disomic controls. Mitochondria were more fused, and O2 consumption was greater in the trisomic induced pluripotent stem cells; however, coupling efficiency and metabolic flexibility were compromised compared with disomic induced pluripotent stem cells. Depletion of RCAN1 from trisomic induced pluripotent stem cells was sufficient to normalize mitochondrial dynamics and function. Conclusions: RCAN1 helps maintain a more interconnected mitochondrial network, and maintaining appropriate RCAN1 levels is important to human health and disease.
Idioma original | English |
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Páginas (desde-hasta) | e20-e33 |
Publicación | Circulation Research |
Volumen | 122 |
N.º | 6 |
DOI | |
Estado | Published - mar. 1 2018 |
Financiación
This work was supported by FONDECYT (11150282 to V. Parra, 1150887 to Z. Pedrozo, and 1161156 to S. Lavandero); FONDAP (15130011 to V. Parra, Z. Pedrozo, and S. Lavandero); PAI Insertion Program, CONICYT (grant 79150007 to V. Parra and S. Lavandero); the National Institutes of Health (NIH; HL-120732, HL-126012, and HL-128215 to J.A. Hill; HL097768 and HL072016 to B.A. Rothermel; PCBC JS 2014/3 01 to V. Parra and J.W. Schneider); American Heart Association (AHA; 13POST16520009 to V. Parra; 16POST30680016 to F. Altamirano; 11POST7950051 to D. Rotter; and 14SFRN20510023 and 14SFRN20670003 to J.A. Hill); Fondation Leducq (11CVD04 to J.A. Hill); and Cancer Prevention and Research Institute of Texas (RP110486P3 to J.A. Hill).
Financiadores | Número del financiador |
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National Institutes of Health | HL-128215, HL-120732, HL072016, HL097768, PCBC JS 2014/3 01 |
National Heart, Lung, and Blood Institute | R01HL126012 |
American Heart Association | 16POST30680016, 13POST16520009, 11POST7950051, 14SFRN20510023, 14SFRN20670003 |
Cancer Prevention and Research Institute of Texas | RP110486P3 |
Fondation Leducq | 11CVD04 |
Comisión Nacional de Investigación Científica y Tecnológica | 79150007 |
Fondo Nacional de Desarrollo Científico y Tecnológico | 11150282, 1161156, 1150887 |
Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias | 15130011 |
ASJC Scopus Subject Areas
- Physiology
- Cardiology and Cardiovascular Medicine