Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location.
Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location.
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DOI：
10.1152/ajpheart.00668.2009
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发表时间：
2010-02
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影响因子：
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通讯作者：
Courtney L. Williamson;E. Dabkowski;Walter A. Baseler;T. Croston;S. Alway;J. Hollander
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作者：
Courtney L. Williamson;E. Dabkowski;Walter A. Baseler;T. Croston;S. Alway;J. Hollander
心血管并发症，如糖尿病性心肌病，是糖尿病相关死亡的主要原因。线粒体特别容易受到糖尿病的破坏性影响，并与糖尿病性心肌病的发病机制有关。心肌线粒体由两个空间上不同的亚群组成，分别称为肌层下线粒体（SSM）和纤维间线粒体（IFM）。本研究的目的是确定亚细胞空间位置是否与糖尿病损伤期间心肌线粒体亚群的凋亡倾向相关。小鼠腹腔注射链脲佐菌素或柠檬酸盐溶液。注射后10周，糖尿病心脏显示caspase-3和caspase-9活性升高，表明凋亡信号通路增强（P < 0.05）。糖尿病IFM的线粒体大小（正向散点）和内部复杂性（侧散点）均降低（P < 0.05），但糖尿病SSM的线粒体大小和内部复杂性均降低（P < 0.05）。线粒体膜电位δ (Psim)在糖尿病性IFM组降低（P < 0.01），而在糖尿病性SSM组无明显差异。糖尿病患者线粒体通透性过渡孔（mPTP）开口比对照组IFM增加（P < 0.05），而糖尿病患者与对照组SSM无差异。mPTP成分检测显示糖尿病IFM中亲环蛋白D增加。此外，糖尿病IFM患者细胞色素c和BcL-2水平降低，Bax水平升高（P < 0.05）。与对照组相比，糖尿病SSM中这些蛋白未见明显变化。这些结果表明糖尿病与IFM细胞凋亡倾向的增强有关，这表明基于亚细胞位置的不同线粒体亚群的细胞凋亡易感性存在差异。
Cardiovascular complications, such as diabetic cardiomyopathy, account for the majority of deaths associated with diabetes mellitus. Mitochondria are particularly susceptible to the damaging effects of diabetes mellitus and have been implicated in the pathogenesis of diabetic cardiomyopathy. Cardiac mitochondria consist of two spatially distinct subpopulations, termed subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The goal of this study was to determine whether subcellular spatial location is associated with apoptotic propensity of cardiac mitochondrial subpopulations during diabetic insult. Swiss Webster mice were subjected to intraperitoneal injection of streptozotocin or citrate saline vehicle. Ten weeks following injection, diabetic hearts displayed increased caspase-3 and caspase-9 activities, indicating enhanced apoptotic signaling (P < 0.05, for both). Mitochondrial size (forward scatter) and internal complexity (side scatter) were decreased in diabetic IFM (P < 0.05, for both) but not in diabetic SSM. Mitochondrial membrane potential (Delta(Psim)) was lower in diabetic IFM (P < 0.01) but not in diabetic SSM. Mitochondrial permeability transition pore (mPTP) opening was increased in diabetic compared with control IFM (P < 0.05), whereas no differences were observed in diabetic compared with control SSM. Examination of mPTP constituents revealed increases in cyclophilin D in diabetic IFM. Furthermore, diabetic IFM possessed lower cytochrome c and BcL-2 levels and increased Bax levels (P < 0.05, for all 3). No significant changes in these proteins were observed in diabetic SSM compared with control. These results indicate that diabetes mellitus is associated with an enhanced apoptotic propensity in IFM, suggesting a differential apoptotic susceptibility of distinct mitochondrial subpopulations based upon subcellular location.