含有蛋白质 5 (TMBIM5) 的跨膜 BAX 抑制剂 1 基序通过影响线粒体蛋白质合成机械来维持线粒体结构、形状和功能

Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial

Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery

Keywords：TMBIM, Cell death, Cell survival, Mitochondria, Mitochondrial metabolism

关键词：TMBIM，细胞死亡，细胞存活，线粒体，线粒体代谢
作者：Seitaj B, Maull F, Zhang L, Wüllner V, Wolf C, Schippers P, La Rovere R, Distler U, Tenzer S, Parys JB, Bultynck G, Methner A
出版期刊：《Cells》 2020/9/23

Abstract：

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson’s disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility. We found that compared to wild type, TMBIM5-knockout cells were smaller and had a slower proliferation rate. In these cells, mitochondria were more fragmented with a vacuolar cristae structure. In addition, the mitochondrial membrane potential was reduced and respiration was attenuated, leading to a reduced mitochondrial ATP generation. TMBIM5 did not associate with Mic10 and Mic60, which are proteins of the mitochondrial contact site and cristae organizing system (MICOS), nor did TMBIM5 knockout affect their expression levels. TMBIM5-knockout cells were more sensitive to apoptosis elicited by staurosporine and BH3 mimetic inhibitors of Bcl-2 and Bcl-XL. An unbiased proteomic comparison identified a dramatic downregulation of proteins involved in the mitochondrial protein synthesis machinery in TMBIM5-knockout cells. We conclude that TMBIM5 is important to maintain the mitochondrial structure and function possibly through the control of mitochondrial biogenesis.

文章摘要：

含有跨膜 Bax 抑制子-1 基序 (TMBIM) 的蛋白质家族在进化上是保守的，并且与细胞死亡易感性有关。唯一具有线粒体定位的成员是 TMBIM5（也称为 GHITM 或 MICS1），它影响嵴组织并与线粒体内膜中的帕金森病相关蛋白 CHCHD2 相关。我们在这里使用 CRISPR-Cas9 介导的敲除 HAP1 细胞来进一步阐明 TMBIM5 在生理学和细胞死亡易感性中的功能。我们发现，与野生型相比，TMBIM5 敲除细胞更小，增殖速度更慢。在这些细胞中，线粒体更加碎片化，具有液泡嵴结构。此外，线粒体膜电位降低，呼吸减弱，导致线粒体 ATP 生成减少。 TMBIM5 与线粒体接触位点和嵴组织系统 (MICOS) 的蛋白质 Mic10 和 Mic60 不相关，TMBIM5 敲除也不影响它们的表达水平。 TMBIM5 敲除细胞对由 Bcl-2 和 Bcl-XL 的星形孢菌素和 BH3 模拟抑制剂引起的细胞凋亡更敏感。一项无偏的蛋白质组学比较发现，在 TMBIM5 敲除细胞中，参与线粒体蛋白质合成机制的蛋白质显着下调。我们得出结论，TMBIM5可能通过控制线粒体生物发生对维持线粒体结构和功能很重要。

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