IF1 limits the apoptotic-signalling cascade by preventing mitochondrial remodelling.
IF1 limits the apoptotic-signalling cascade by preventing mitochondrial remodelling.
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DOI：
10.1038/cdd.2012.163
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发表时间：
2013-05
影响因子：
12.4
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中科院分区：
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线粒体结构在能量转换和细胞死亡调节中发挥着核心作用。我们之前已经证明，IF1 可以保护细胞免遭坏死性细胞死亡，并通过促进 F1Fo-ATP 合酶的寡聚化来支持嵴结构。由于 IF1 在大部分人类癌症中表达上调，我们在这里探讨了它对细胞凋亡进程的贡献，并报告说，相对于 F1Fo-ATP 合酶，IF1 表达增加可保护细胞免于细胞凋亡。我们发现 IF1 表达作为细胞色素 c (Cyt c) 释放的检查点，从而完成细胞凋亡程序。我们发现细胞凋亡的进展涉及由下列因素介导的放大途径：(i) Cyt c 依赖性释放 ER Ca2+，(ii) Ca2+ 依赖性 GTPase Dynamin 相关蛋白 1 (Drp1) 募集，(iii) Bax 插入线粒体外膜，以及 (iv) Cyt c 进一步释放。该途径因 IF1 的抑制而加速，并因 IF1 的过度表达而延迟。 IF1 过表达与线粒体形态和超微结构的保存相关，这与 IF1 作为内膜结构决定因素的核心作用以及线粒体超微结构在 Cyt c 释放调节中的作用一致。这些数据表明 IF1 是一种抗细胞凋亡和潜在的致瘤因子，并且可能是化疗反应的有价值的预测因子。
Mitochondrial structure has a central role both in energy conversion and in the regulation of cell death. We have previously shown that IF1 protects cells from necrotic cell death and supports cristae structure by promoting the oligomerisation of the F1Fo-ATPsynthase. As IF1 is upregulated in a large proportion of human cancers, we have here explored its contribution to the progression of apoptosis and report that an increased expression of IF1, relative to the F1Fo-ATPsynthase, protects cells from apoptotic death. We show that IF1 expression serves as a checkpoint for the release of Cytochrome c (Cyt c) and hence the completion of the apoptotic program. We show that the progression of apoptosis engages an amplification pathway mediated by: (i) Cyt c-dependent release of ER Ca2+, (ii) Ca2+-dependent recruitment of the GTPase Dynamin-related protein 1 (Drp1), (iii) Bax insertion into the outer mitochondrial membrane and (iv) further release of Cyt c. This pathway is accelerated by suppression of IF1 and delayed by its overexpression. IF1 overexpression is associated with the preservation of mitochondrial morphology and ultrastructure, consistent with a central role for IF1 as a determinant of the inner membrane architecture and with the role of mitochondrial ultrastructure in the regulation of Cyt c release. These data suggest that IF1 is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy.