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.
authors.affiliation: Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: J Craig
authors.initials: JC
authors.lastname: Hunter
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Machikas
authors.forename: Donna H
authors.initials: DH
authors.lastname: Korzick
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008929:Mitochondria, Heart / Q000378:metabolism*; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D002118:Calcium