Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death
Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death
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DOI：
10.1128/mcb.01535-06
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发表时间：
2007-02-01
影响因子：
5.3
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
--
作者：
Brunelle, Joslyn K.;Shroff, Emelyn H.;Chandel, Navdeep S.
细胞是如何在缺氧的情况下死亡的还不清楚。在这里，我们报告了缺乏Bax和Bak或caspase-9的细胞不会经历缺氧诱导的细胞死亡。然而，由于线粒体活性氧的产生，caspase-9缺失细胞不能在再氧化中存活。Bim、Bid、Puma、Noxa、Bad、caspase-2或缺氧诱导因子1 β （Bax或Bak的潜在上游调节因子）的个体缺失并不能阻止缺氧诱导的细胞死亡。缺氧触发Bax/Bak活化上游Mcl-1蛋白的丢失。含有线粒体DNA细胞色素b 4碱基对缺失的细胞（[rho(-)]细胞）和整个线粒体DNA缺失的细胞（[rho(0)]细胞）的氧化磷酸化功能不全，在缺氧条件下表现出Mcl-1蛋白的缺失。与[rho-]细胞相比，[rho(0)]细胞在缺氧条件下没有死亡。然而，[rho(0)]细胞在Bad BH3肽（Bcl-X-L/Bcl-2蛋白的抑制剂）存在下确实发生了细胞死亡。这些结果表明，尽管由于Bcl-X-L/Bcl-2蛋白残留的促生存活性导致Mcl-1蛋白丢失，但[rho(0)]细胞在缺氧条件下仍能存活。综上所述，这些结果表明缺氧诱导的细胞死亡需要Mcl-1蛋白的丢失和电子传递链的抑制来抑制Bcl-X-L/Bcl-2蛋白。
How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1 beta, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(-)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho-] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X-L/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X-L/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X-L/Bcl-2 proteins.