ChChd3 是一种线粒体内膜蛋白，对于维持嵴完整性和线粒体功能至关重要。,Journal of Biological Chemistry

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ChChd3 是一种线粒体内膜蛋白，对于维持嵴完整性和线粒体功能至关重要。
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2011 Jan 28 , DOI: 10.1074/jbc.m110.171975
Manjula Darshi ₁ , Vincent L Mendiola , Mason R Mackey , Anne N Murphy , Antonius Koller , Guy A Perkins , Mark H Ellisman , Susan S Taylor

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线粒体内膜 (IM) 通过在嵴膜上承载氧化磷酸化复杂机制，充当 ATP 生产的场所。嵴结构的破坏与多种心血管和神经退行性疾病有关。在这里，我们表征了 ChChd3，这是一种先前确定的未知功能的 PKA 底物（Schauble, S., King, CC, Darshi, M., Koller, A., Shah, K. 和 Taylor, SS (2007) J. Biol. Chem. 282, 14952-14959)，并表明它对于维持嵴完整性和线粒体功能至关重要。在线粒体中，ChChd3 是面向膜间隙的 IM 的外周蛋白。在 HeLa 细胞中对 ChChd3 的 RNAi 敲低导致线粒体碎片化、OPA1 蛋白水平降低和融合受损，和细胞核周围的线粒体聚集以及生长速度降低。耗氧量和糖酵解速率都受到严格限制。这些细胞的超微结构分析揭示了异常的线粒体 IM 结构，具有破碎和管状嵴或嵴丢失，以及嵴膜减少。此外，嵴交界处开口直径减小到 50%，表明在没有 ChChd3 的情况下嵴重塑。对 ChChd3 结合蛋白的分析表明，ChChd3 与调节嵴形态的 IM 蛋白 mitofilin 和 OPA1 以及外膜蛋白 Sam50（调节外膜上 β-桶蛋白的导入和组装）相互作用。

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ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity and mitochondrial function.

The mitochondrial inner membrane (IM) serves as the site for ATP production by hosting the oxidative phosphorylation complex machinery most notably on the crista membranes. Disruption of the crista structure has been implicated in a variety of cardiovascular and neurodegenerative diseases. Here, we characterize ChChd3, a previously identified PKA substrate of unknown function (Schauble, S., King, C. C., Darshi, M., Koller, A., Shah, K., and Taylor, S. S. (2007) J. Biol. Chem. 282, 14952-14959), and show that it is essential for maintaining crista integrity and mitochondrial function. In the mitochondria, ChChd3 is a peripheral protein of the IM facing the intermembrane space. RNAi knockdown of ChChd3 in HeLa cells resulted in fragmented mitochondria, reduced OPA1 protein levels and impaired fusion, and clustering of the mitochondria around the nucleus along with reduced growth rate. Both the oxygen consumption and glycolytic rates were severely restricted. Ultrastructural analysis of these cells revealed aberrant mitochondrial IM structures with fragmented and tubular cristae or loss of cristae, and reduced crista membrane. Additionally, the crista junction opening diameter was reduced to 50% suggesting remodeling of cristae in the absence of ChChd3. Analysis of the ChChd3-binding proteins revealed that ChChd3 interacts with the IM proteins mitofilin and OPA1, which regulate crista morphology, and the outer membrane protein Sam50, which regulates import and assembly of beta-barrel proteins on the outer membrane. Knockdown of ChChd3 led to almost complete loss of both mitofilin and Sam50 proteins and alterations in several mitochondrial proteins, suggesting that ChChd3 is a scaffolding protein that stabilizes protein complexes involved in maintaining crista architecture and protein import and is thus essential for maintaining mitochondrial structure and function.

更新日期：2017-01-31

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