Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart.
Mitochondrial Ca(2+) plays important roles in the regulation of energy metabolism and cellular Ca(2+) homeostasis. In this study, we characterized mitochondrial Ca(2+) accumulation in Syrian hamster hearts with hereditary cardiomyopathy (strain BIO 14.6). Exposure of isolated mitochondria from 70 nM to 30 microM Ca(2+) ([Ca(2+)](o)) caused a concentration-dependent increase in intramitochondrial Ca(2+) concentrations ([Ca(2+)](m)). The [Ca(2+)](m) was significantly lower in cardiomyopathic (CMP) hamsters than in healthy hamsters when [Ca(2+)](o) was higher than 1 microM and a decrease of about 52% was detected at [Ca(2+)](o) of 30 microM (916 +/- 67 nM vs 1,932 +/- 132 nM in control). A possible mechanism responsible for the decreased mitochondrial Ca(2+) uptake in CMP hamsters is the depolarization of mitochondrial membrane potential (Delta psi (m)). Using a tetraphenylphosphonium (TPP(+)) electrode, the measured Delta psi (m) in failing heart mitochondria was -136 +/- 1.5 mV compared with -159 +/- 1.3 mV in controls. Analyses of mitochondrial respiratory chain demonstrated a significant impairment of complex I and complex IV activities in failing heart mitochondria. In summary, a less negative Delta psi (m) resulting from defects in the respiratory chain may lead to attenuated mitochondrial Ca(2+) accumulation, which in turn may contribute to the depressed energy production and myocardial contractility in this model of heart failure. In addition to other known impairments of ion transport in sarcoplasmic reticulum and plasma membrane, results from this paper on mitochondrial dysfunctions expand our understanding of the molecular mechanisms leading to heart failure.
Lin
Lin
L
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA.
Sharma
Virendra K
VK
Sheu
Shey-Shing
SS
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004579:Electron Transport; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D017136:Ion Transport; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008647:Mesocricetus; D008929:Mitochondria, Heart / Q000378:metabolism*
D002118:Calcium