Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes
Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes
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DOI：
10.1038/sj.cdd.4401553
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发表时间：
2005-03-01
影响因子：
12.4
通讯作者：
Avadhani, NG
中科院分区：
文献类型：
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作者：
Biswas, G;Anandatheerthavarada, HK;Avadhani, NG
在这项研究中，我们发现部分线粒体 DNA (mtDNA) 耗竭（线粒体应激）会诱导 C2C12 成肌细胞对星形孢菌素 (STP) 介导的细胞凋亡产生抵抗。 MtDNA 耗尽的细胞显示促凋亡蛋白（Bax、BAD 和 Bid）增加 3-4 倍，抗凋亡 Bcl-2 显着增加，p21 Bid 向活性 tBid 的加工减少。在含有接近正常线粒体DNA水平的恢复细胞中，蛋白质水平以及经历STP介导的细胞凋亡的能力都得到恢复，并且线粒体跨膜电位也得到恢复。细胞凋亡的抑制与线粒体内膜中 Bax、Bid 和 BAD 的隔离、Bcl-2 和 Bcl-X-L 的增加以及无法处理 p21 Bid 密切相关。这些因素以及 caspase 3、9 和 8 激活的减少可能是线粒体应激诱导的细胞凋亡抵抗的原因。我们的结果表明，线粒体 DNA 耗尽的 C2C12 细胞的高度增殖和侵袭行为与其对细胞凋亡的抵抗有关。
In this study, we show that partial mitochondrial DNA (mtDNA) depletion (mitochondrial stress) induces resistance to staurosporine (STP)-mediated apoptosis in C2C12 myoblasts. MtDNA-depleted cells show a 3-4- fold increased proapoptotic proteins (Bax, BAD and Bid), markedly increased antiapoptotic Bcl-2, and reduced processing of p21 Bid to active tBid. The protein levels and also the ability to undergo STP-mediated apoptosis were restored in reverted cells containing near-normal mtDNA levels and restored mitochondrial transmembrane potential. Inhibition of apoptosis closely correlated with sequestration of Bax, Bid and BAD in the mitochondrial inner membrane, increased Bcl-2 and Bcl-X-L, and inability to process p21 Bid. These factors, together with the reduced activation of caspases 3, 9 and 8 are possible causes of mitochondrial stress-induced resistance to apoptosis. Our results suggest that a highly proliferative and invasive behavior of mtDNA-depleted C2C12 cells is related to their resistance to apoptosis.