Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart.
Mitochondrial calcium overload has been implicated in the irreversible damage of reperfused heart. Accordingly, we studied the effect of an oxygen-bridged dinuclear ruthenium amine complex (Ru360), which is a selective and potent mitochondrial calcium uniporter blocker, on mitochondrial dysfunction and on the matrix free-calcium concentration in mitochondria isolated from reperfused rat hearts. The perfusion of Ru360 maintained oxidative phosphorylation and prevented opening of the mitochondrial permeability transition pore in mitochondria isolated from reperfused hearts. We found that Ru360 perfusion only partially inhibited the mitochondrial calcium uniporter, maintaining the mitochondrial matrix free-calcium concentration at basal levels, despite high concentrations of cytosolic calcium. Additionally, we observed that perfused Ru360 neither inhibited Ca2+ cycling in the sarcoplasmic reticulum nor blocked ryanodine receptors, implying that the inhibition of ryanodine receptors cannot explain the protective effect of Ru360 in isolated hearts. We conclude that the maintenance of postischemic myocardial function correlates with an incomplete inhibition of the mitochondrial calcium uniporter. Thus, the chemical inhibition by this molecule could be an approach used to prevent heart injury during reperfusion.
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México D.F., México.
Gerardo
G
de Jesús García-Rivas
Agustín
A
Guerrero-Hernández
Guadalupe
G
Guerrero-Serna
José S
JS
Rodríguez-Zavala
Cecilia
C
Zazueta
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D003600:Cytosol / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012428:Ruthenium / Q000378:metabolism; D017975:Ruthenium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C112020:Ru 360; D017975:Ruthenium Compounds; D019837:Ryanodine Receptor Calcium Release Channel; C034703:mitochondrial calcium uniporter; D012428:Ruthenium; D002118:Calcium