Gender modulation of Ca(2+) uptake in cardiac mitochondria.
BACKGROUND
Mitochondrial calcium overload is an important factor in defining ischemia/reperfusion injury. Since pre-menopausal women are relatively protected from ischemia and heart disease, we tested the hypothesis that gender differences alter Ca(2+) handling in rat cardiac mitochondria.


METHODS
Using cardiac mitochondria isolated from male, female, and ovariectomized Sprague-Dawley rats, we measured mitochondrial calcium transport, redox state, and membrane potential (Deltapsi(m)) during exposure to a calcium bolus. Redox state was modulated using either succinate (S) or succinate and pyruvate (SP) as substrates.


RESULTS
Net Ca(2+) uptake rates were significantly lower in female than male mitochondria using SP, substrate conditions that resulted in a lower redox state (NADH/NAD(+)). Inhibition of the mitochondrial transition pore (MTP) using cyclosporin A showed significantly lower net Ca(2+) uptake in both substrate solutions when mitochondria from female and ovariectomized animals were compared to males, a finding consistent with gender modulation of the mitochondrial uniporter. Blockade of the Ca(2+) uniporter by ruthenium red abolished gender or substrate solution differences in calcium release. While there were no significant differences in resting Deltapsi(m), or Deltapsi(m) following Ca(2+) addition, 80% of female samples recovered from Ca(2+)-induced depolarization compared to 57% and 43% of male and ovariectomized animals, respectively.


CONCLUSIONS
Mitochondria from female hearts have lower Ca(2+) uptake rates under physiologic substrate solutions (succinate/pyruvate) and are able to appropriately maintain DeltaYm under conditions of high [Ca(2+)]. These differences are consistent with gender modulation of the Ca(2+) uniporter and may be a mechanism by which female myocardium suffers less injury with ischemia/reperfusion.
Division of Cardiovascular Medicine, University of California, One Shields Avenue, TB 172 Bioletti Way, Davis, CA 95616, USA.
Yehuda
Y
Arieli
Hemamalini
H
Gursahani
Matt M
MM
Eaton
Lisa A
LA
Hernandez
Saul
S
Schaefer
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D051381:Rats; D012737:Sex Factors
D009243:NAD; D016572:Cyclosporine; D002118:Calcium