Adenine nucleotide translocase-1 induces cardiomyocyte death through upregulation of the pro-apoptotic protein Bax.
Adenine nucleotide translocase-1 induces cardiomyocyte death through upregulation of the pro-apoptotic protein Bax.
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腺嘌呤核苷酸转位酶-1 通过上调促凋亡蛋白 Bax 诱导心肌细胞死亡。
DOI：
10.1016/j.yjmcc.2009.01.016
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发表时间：
2009-06
影响因子：
5
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
--
作者：
Baines, Christopher P.;Molkentin, Jeffery D.
腺嘌呤核苷酸移位酶（ANT）的过表达已被证明在几种细胞类型中具有细胞毒性。虽然ANT最初被认为是线粒体通透性转换（MPT）孔的关键组成部分，但最近的数据表明，情况可能并非如此。因此，我们假设ANT的细胞毒性作用是通过另一种机制，独立于MPT孔。用编码ANT 1的腺病毒感染培养的新生心肌细胞可诱导细胞死亡的基因剂量依赖性增加。然而，ANT 1过表达未能诱导MPT，并且MPT孔的药理学或遗传抑制均不能防止ANT 1诱导的细胞死亡。这些数据表明，ANT 1诱导的死亡通过MPT孔非依赖性途径进行。令人惊讶的是，我们观察到Bax（一种促凋亡Bcl蛋白）的蛋白水平在ANT 1感染的心肌细胞中持续升高。从ANT 1感染的心肌细胞分离的膜表现出显着增加的膜插入Bax的量，和免疫细胞化学显示增加的Bax激活ANT 1感染的心肌细胞。与Bax拮抗剂Bcl 2的共表达能够大大降低ANT 1诱导的细胞死亡的程度。此外，Bax/Bak缺陷的成纤维细胞对ANT 1过表达的细胞毒性作用具有抗性。有趣的是，ANT 1过表达也与活性氧（ROS）的产生增加有关，抗氧化剂MnTBAP能够显着减弱ANT 1诱导的Bax上调和细胞死亡。总之，这些数据表明，ANT介导的细胞死亡，而不是通过MPT孔，而是通过ROS依赖性上调和激活Bax。
Overexpression of the adenine nucleotide translocase (ANT) has been shown to be cytotoxic in several cell types. Although ANT was originally proposed to be a critical component of the mitochondrial permeability transition (MPT) pore, recent data have suggested that this may not be the case. We therefore hypothesized that the cytotoxic actions of ANT are through an alternative mechanism, independent of the MPT pore. Infection of cultured neonatal cardiomyocytes with an ANT1-encoding adenovirus induced a gene dosage-dependent increase in cell death. However, ANT1 overexpression failed to induce MPT, and neither pharmacological nor genetic inhibition of the MPT pore was able to prevent ANT1-induced cell death. These data suggested that ANT1-induced death progressed through an MPT pore-independent pathway. Somewhat surprisingly, we observed that protein levels of Bax, a pro-apoptotic Bcl protein, were consistently elevated in ANT1-infected cardiomyocytes. Membranes isolated from ANT1-infected myocytes exhibited significantly increased amounts of membrane-inserted Bax, and immunocytochemistry revealed increased Bax activation in ANT1-infected myocytes. Co-expression with the Bax antagonist Bcl2 was able to greatly reduce the degree of ANT1-induced cell death. Furthermore, Bax/Bak-deficient fibroblasts were resistant to the cytotoxic effects of ANT1 overexpression. Interestingly, ANT1 overexpression was also associated with enhanced production of reactive oxygen species (ROS), and the antioxidant MnTBAP was able to significantly attenuate both the ANT1-induced upregulation of Bax and cell death. Taken together, these data indicate that ANT mediates cell death, not through the MPT pore, but rather via a ROS-dependent upregulation and activation of Bax.
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影响因子：
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作者：
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通讯作者：
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