Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
J Biol Chem. 2012 Mar 2;287(10):7411-26. doi: 10.1074/jbc.M111.277103. Epub 2012 Jan 6.
The structural integrity of mitochondrial cristae is crucial for mitochondrial functions; however, the molecular events controlling the structural integrity and biogenesis of mitochondrial cristae remain to be fully elucidated. Here, we report the functional characterization of a novel mitochondrial protein named CHCM1 (coiled coil helix cristae morphology 1)/CHCHD6. CHCM1/CHCHD6 harbors a coiled coil helix-coiled coil helix domain at its C-terminal end and predominantly localizes to mitochondrial inner membrane. CHCM1/CHCHD6 knockdown causes severe defects in mitochondrial cristae morphology. The mitochondrial cristae in CHCM1/CHCHD6-deficient cells become hollow with loss of structural definitions and reduction in electron-dense matrix. CHCM1/CHCHD6 depletion also leads to reductions in cell growth, ATP production, and oxygen consumption. CHCM1/CHCHD6 through its C-terminal end strongly and directly interacts with the mitochondrial inner membrane protein mitofilin, which is known to also control mitochondrial cristae morphology. CHCM1/CHCHD6 also interacts with other mitofilin-associated proteins, including DISC1 and CHCHD3. Knockdown of CHCM1/CHCHD6 reduces mitofilin protein levels; conversely, mitofilin knockdown leads to reduction in CHCM1 levels, suggesting coordinate regulation between these proteins. Our results further indicate that genotoxic anticancer drugs that induce DNA damage down-regulate CHCM1/CHCHD6 expression in multiple human cancer cells, whereas mitochondrial respiratory chain inhibitors do not affect CHCM1/CHCHD6 levels. CHCM1/CHCHD6 knockdown in human cancer cells enhances chemosensitivity to genotoxic anticancer drugs, whereas its overexpression increases resistance. Collectively, our results indicate that CHCM1/CHCHD6 is linked to regulation of mitochondrial cristae morphology, cell growth, ATP production, and oxygen consumption and highlight its potential as a possible target for cancer therapeutics.
线粒体嵴的结构完整性对于线粒体功能至关重要；然而，控制线粒体嵴的结构完整性和生物发生的分子事件仍有待充分阐明。在这里，我们报告了一种新型线粒体蛋白 CHCM1（卷曲螺旋-螺旋-卷曲结构域嵴形态 1）/CHCHD6 的功能特征。CHCM1/CHCHD6 在其 C 端末端含有一个卷曲螺旋-螺旋-螺旋结构域，主要定位于线粒体内膜。CHCM1/CHCHD6 敲低导致线粒体嵴形态严重缺陷。CHCM1/CHCHD6 缺陷细胞中的线粒体嵴变得中空，失去结构定义，电子致密基质减少。CHCM1/CHCHD6 耗竭还导致细胞生长、ATP 产生和耗氧量减少。CHCM1/CHCHD6 通过其 C 端末端与已知控制线粒体嵴形态的线粒体内膜蛋白 mitofilin 强烈且直接相互作用。CHCM1/CHCHD6 还与其他 mitofilin 相关蛋白相互作用，包括 DISC1 和 CHCHD3。CHCM1/CHCHD6 敲低降低了 mitofilin 蛋白水平；相反，mitofilin 敲低导致 CHCM1 水平降低，表明这些蛋白之间存在协调调节。我们的结果进一步表明，诱导 DNA 损伤的致瘤性抗癌药物会下调多种人类癌细胞中的 CHCM1/CHCHD6 表达，而线粒体呼吸链抑制剂不会影响 CHCM1/CHCHD6 水平。在人类癌细胞中敲低 CHCM1/CHCHD6 可增强对致瘤性抗癌药物的化疗敏感性，而过表达 CHCM1/CHCHD6 则可增加耐药性。总之，我们的研究结果表明，CHCM1/CHCHD6 与调节线粒体嵴形态、细胞生长、ATP 产生和耗氧量有关，并强调了其作为癌症治疗潜在靶点的可能性。
