TY - JOUR
T1 - Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart
AU - Hunter, J. Craig
AU - MacHikas, Alexandra M.
AU - Korzick, Donna H.
N1 - Funding Information:
The authors thank Dr. Sabzali Javadov (University of Puerto Rico) for his expert methodological advice. This work was supported by National Heart, Lung, and Blood Institute ( RO1 HL091097 [D.H.K.], RO1 HL091097-01A2S1 [D.H.K.]) and National Institute on Alcohol Abuse and Alcoholism ( RC2 AA019403 [D.H.K.]) at the National Institutes of Health. J.C. Hunter contributed to all aspects of this manuscript including: design of the studies; collection, analysis, and interpretation of the data; drafting and editing the manuscript; and final submission. A.M. Machikas assisted with: data collection, analysis, and interpretation; drafting and critically revising the manuscript. D.H. Korzick contributed to: conception, design, and procurement of funds for the study as well as interpretation of the data; drafting and critically revising the manuscript.
PY - 2012/6
Y1 - 2012/6
N2 - Background: Cardiovascular disease mortality increases rapidly after menopause by poorly defined mechanisms. Objective: Because mitochondrial function and Ca 2+ sensitivity are important regulators of cell death after myocardial ischemia, we sought to determine whether aging and/or estrogen deficiency (ovariectomy) increased mitochondrial Ca 2+ sensitivity. Methods: Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6 months; n = 26) and aged (24 months; n = 25), intact or ovariectomized female rats using the substrates α-ketoglutarate/malate (complex I); succinate/rotenone (complex II); ascorbate/N,N,N′,N′- tetramethyl-p-phenylenediamine/antimycin (complex IV). State 2 and 3 respiration was initiated by sequential addition of mitochondria and adenosine diphosphate. Ca 2+ sensitivity was assessed by Ca 2+-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered intraperitoneally 45 minutes before euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) α activation. Results: Aging decreased the respiratory control index (RCI; state 3/state 2) for complexes I and II by 12% and 8%, respectively, independent of ovary status (P < 0.05). Of interest, Ca 2+ induced a greater decrease (18%-30%; P < 0.05) in complex I state 3 respiration in aged and ovariectomized animals, and mitochondrial swelling occurred twice as quickly in aged (vs adult) female rats (P < 0.05). Pretreatment with PPT increased RCI by 8% and 7% at complexes I and II, respectively (P < 0.05) but surprisingly increased Ca 2+ sensitivity. Conclusions: Age-dependent decreases in RCI and sensitization to Ca 2+ may explain in part the age-associated reductions in female ischemic tolerance; however, protection afforded by ER agonism involves more complex mechanisms.
AB - Background: Cardiovascular disease mortality increases rapidly after menopause by poorly defined mechanisms. Objective: Because mitochondrial function and Ca 2+ sensitivity are important regulators of cell death after myocardial ischemia, we sought to determine whether aging and/or estrogen deficiency (ovariectomy) increased mitochondrial Ca 2+ sensitivity. Methods: Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6 months; n = 26) and aged (24 months; n = 25), intact or ovariectomized female rats using the substrates α-ketoglutarate/malate (complex I); succinate/rotenone (complex II); ascorbate/N,N,N′,N′- tetramethyl-p-phenylenediamine/antimycin (complex IV). State 2 and 3 respiration was initiated by sequential addition of mitochondria and adenosine diphosphate. Ca 2+ sensitivity was assessed by Ca 2+-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered intraperitoneally 45 minutes before euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) α activation. Results: Aging decreased the respiratory control index (RCI; state 3/state 2) for complexes I and II by 12% and 8%, respectively, independent of ovary status (P < 0.05). Of interest, Ca 2+ induced a greater decrease (18%-30%; P < 0.05) in complex I state 3 respiration in aged and ovariectomized animals, and mitochondrial swelling occurred twice as quickly in aged (vs adult) female rats (P < 0.05). Pretreatment with PPT increased RCI by 8% and 7% at complexes I and II, respectively (P < 0.05) but surprisingly increased Ca 2+ sensitivity. Conclusions: Age-dependent decreases in RCI and sensitization to Ca 2+ may explain in part the age-associated reductions in female ischemic tolerance; however, protection afforded by ER agonism involves more complex mechanisms.
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U2 - 10.1016/j.genm.2012.04.001
DO - 10.1016/j.genm.2012.04.001
M3 - Article
C2 - 22555015
AN - SCOPUS:84862224682
SN - 1550-8579
VL - 9
SP - 197
EP - 206
JO - Gender Medicine
JF - Gender Medicine
IS - 3
ER -
