Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-β exposure
Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-β exposure
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DOI：
10.2337/diabetes.52.6.1449
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发表时间：
2003-06-01
期刊：
影响因子：
7.7
通讯作者：
Oliveira, CR
中科院分区：
文献类型：
--
作者：
Moreira, PI;Santos, MS;Oliveira, CR
本研究测定了正常Wistar和GK糖尿病大鼠不同年龄(1.5、12和24月龄)脑线粒体的呼吸指标(呼吸控制比[RCR]和ADP/O比)、线粒体跨膜电位(DeltaPsim)、复极延迟期、复极水平、ATP/ADP比值和对脑线粒体通透性转换孔的诱导。并分析了50mumol/L Abeta(25-35)或2mumol/L Abeta(1-40)的淀粉样β多肽对线粒体功能的影响。糖尿病小鼠衰老后，脑线粒体RCR、ADP/O和ATP/ADP比值降低，复极延迟期增加。老年糖尿病大鼠脑线粒体更容易产生通透性转换孔，即24月龄糖尿病大鼠脑线粒体钙离子积累量(20mumol/L)明显少于12月龄大鼠(50mumol/L)和1.5月龄大鼠(100mumol/L)。在50 Mumol/L Abeta(25-35)或2 Mumol/L Abeta(1-40)存在下，与年龄相关的线粒体效应被增强。这些结果表明，衰老和/或淀粉样β-肽等神经毒性物质的存在会加剧糖尿病相关的线粒体功能障碍，这支持了糖尿病和衰老是这些肽诱导的神经变性的危险因素的观点。
This study evaluated the respiratory indexes (respiratory control ratio [RCR] and ADP/O ratio), mitochondrial transmembrane potential (DeltaPsim), repolarization lag phase, repolarization level, ATP/ADP ratio, and induction of the permeability transition pore of brain mitochondria isolated from normal Wistar and GK diabetic rats of different ages (1.5, 12, and 24 months of age). The effect of amyloid beta-peptides, 50 mumol/l Abeta(25-35) or 2 mumol/l Abeta(1-40), on mitochondrial function was also analyzed. Aging of diabetic mice induced a decrease in brain mitochondrial RCR, ADP/O, and ATP/ADP ratios but induced an increase in the repolarization lag phase. Brain mitochondria from older diabetic rats were more prone to the induction of the permeability transition pore, i.e., mitochondria from 24-month-old diabetic rats accumulated much less Ca2+ (20 mumol/l) than those isolated from 12-month-old rats (50 mumol/l) or 1.5-month-old rats (100 mumol/l). In the presence of 50 mumol/l Abeta(25-35) or 2 mumol/l Abeta(1-40), age-related mitochondrial effects were potentiated. These results indicate that diabetes-related mitochondrial dysfunction is exacerbated by aging and/or by the presence of neurotoxic agents such as amyloid beta-peptides, supporting the idea that diabetes and aging are risk factors for the neuro-degeneration induced by these peptides.