Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart

J. Craig Hunter, Alexandra M. MacHikas, Donna Hope Korzick

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalGender Medicine
Volume9
Issue number3
DOIs
StatePublished - Jun 1 2012

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sensitization
menopause
euthanasia
activation
tolerance
mortality
animal
Disease
death

All Science Journal Classification (ASJC) codes

  • Gender Studies

Cite this

@article{72224585caa44c23a9defc624f01fc9e,
title = "Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart",
abstract = "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.",
author = "Hunter, {J. Craig} and MacHikas, {Alexandra M.} and Korzick, {Donna Hope}",
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Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart. / Hunter, J. Craig; MacHikas, Alexandra M.; Korzick, Donna Hope.

In: Gender Medicine, Vol. 9, No. 3, 01.06.2012, p. 197-206.

Research output: Contribution to journalArticle

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AU - Hunter, J. Craig

AU - MacHikas, Alexandra M.

AU - Korzick, Donna Hope

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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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