Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart.
Age-dependent reductions in mitochondrial respiration are exacerbated by calcium in the female rat heart.
复制标题
DOI：
10.1016/j.genm.2012.04.001
复制
发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Korzick DH
中科院分区：
文献类型：
--
作者：
Hunter JC;Machikas AM;Korzick DH
绝经后心血管疾病死亡率迅速增加，机制不明确。由于线粒体功能和Ca2+敏感性是心肌缺血后细胞死亡的重要调节因子，我们试图确定衰老和/或雌激素缺乏（ovx）是否会增加线粒体Ca2+敏感性。用底物α-酮戊二酸/苹果酸（复合物I）对成年（6个月，n=26）和老年（24个月，n=25）完整或去卵巢的雌性大鼠分离的心室线粒体进行线粒体呼吸测定；琥珀酸盐/鱼藤酮（配合物II）；抗坏血酸/TMPD/抗霉素（复合物IV）。状态2和状态3呼吸是通过线粒体和ADP的顺序添加而启动的。通过Ca2+诱导的去能量线粒体肿胀和状态3呼吸减少来评估Ca2+敏感性。在安乐死前45分钟给予丙基吡唑三醇（PPT），通过激活雌激素受体(ER) α来评估线粒体保护作用。衰老使复合体I和复合体II的呼吸控制指数（RCI；状态3/状态2）分别下降12%和8%，与卵巢状态无关（p<0.05）。有趣的是，Ca2+诱导老年和ovx动物复合物I状态3呼吸的更大降低（18-30%;p<0.05），老年雌性大鼠线粒体肿胀的速度是成年大鼠的两倍（p<0.05）。PPT预处理使复合物I和II的RCI分别提高了8%和7% (p<0.05)，但出乎意料地增加了Ca2+敏感性。年龄相关的RCI下降和Ca2+敏化可能部分解释了女性缺血耐受性的年龄相关降低；然而，内质网激动作用提供的保护涉及更复杂的机制。
Cardiovascular disease mortality increases rapidly following menopause by poorly defined mechanisms. Since mitochondrial function and Ca2+ sensitivity are important regulators of cell death following myocardial ischemia, we sought to determine if aging and/or estrogen deficiency (ovx) increased mitochondrial Ca2+ sensitivity. Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6mo; n=26) and aged (24mo; n=25), intact or ovariectomized female rats using the substrates: α-ketoglutarate/malate (Complex I); succinate/rotenone (Complex II); ascorbate/TMPD/Antimycin (Complex IV). State 2 and State 3 respiration was initiated by sequential addition of mitochondria and ADP. Ca2+ sensitivity was assessed by Ca2+-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered i.p. 45 min prior to euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) α activation. 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, Ca2+ induced a greater decrease (18–30%; p<0.05) in Complex I state 3 respiration in aged and ovx 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 Ca2+ sensitivity. Age-dependent decreases in RCI and sensitization to Ca2+ may explain in part the age-associated reductions in female ischemic tolerance; however protection afforded by ER agonism involves more complex mechanisms.
登录
查看更多内容
影响因子：
4.8
作者：
Judge, S;Jang, YM;Leeuwenburgh, C
通讯作者：
Leeuwenburgh, C
影响因子：
4.3
作者：
Bratic, Ivana;Trifunovic, Aleksandra
通讯作者：
Trifunovic, Aleksandra
影响因子：
3.9
作者：
Kwong, LK;Sohal, RS
通讯作者：
Sohal, RS
影响因子：
5.3
作者：
Preston, Claudia C.;Oberlin, Andrew S.;Jahangir, Arshad
通讯作者：
Jahangir, Arshad
影响因子：
3.5
作者：
Morkuniene, R;Jekabsone, A;Borutaite, V
通讯作者：
Borutaite, V