VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function.
VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function.
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DOI：
10.3389/fonc.2018.00388
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发表时间：
2018
影响因子：
4.7
通讯作者：
Ashcroft M
中科院分区：
文献类型：
--
作者：
Briston T;Stephen JM;Thomas LW;Esposito C;Chung YL;Syafruddin SE;Turmaine M;Maddalena LA;Greef B;Szabadkai G;Maxwell PH;Vanharanta S;Ashcroft M
线粒体功能失调与包括肾病和癌症在内的多种疾病的病理学相关。因此，研究线粒体功能的调节剂是特别感兴趣的。先前的研究表明，von Hippel-Lindau肿瘤抑制蛋白（pVHL）调节线粒体生物合成和呼吸链功能。pVHL作为二聚体转录因子的缺氧诱导因子（HIF）家族的α-亚基的E3-泛素连接酶而最为人所知。在常氧条件下，pVHL识别并结合羟基化HIF-α（HIF-1α和HIF-2α），靶向其进行泛素化和蛋白酶体降解。通过这种方式，HIF转录活性被严格控制在HIF-α蛋白稳定性水平。至少80%的肾透明细胞癌表现出VHL基因失活，这导致HIF-α蛋白稳定和组成性HIF激活。肾癌中组成性HIF活化驱动肿瘤进展和转移。野生型VHL蛋白（pVHL）在pVHL缺陷型肾癌细胞中的重建不仅抑制HIF激活和肿瘤生长，而且通过尚未完全阐明的机制增强线粒体呼吸链功能。在此，我们发现pVHL在pVHL缺陷的786 O和RCC 10肾癌细胞中重新表达时调节线粒体功能，与其调节HIF-α不同。通过pVHL再表达，CHCHD 4的表达升高，CHCHD 4是参与膜间隙（IMS）内线粒体蛋白质输入的二硫化物中继系统（DRS）的关键组分，同时复合物I（NDUFB 10）和复合物IV（mtCO-2和考克斯IV）的呼吸链亚基的表达增强。这些变化与耗氧率（OCR）增加和葡萄糖和谷氨酰胺代谢的动态变化相关。在786 O细胞中，HIF-2α的敲低也导致OCR增加，CHCHD 4、NDUFB 10和COXIV的表达增加。pVHL突变体蛋白（R200 W、N78 S、D126 N和S183 L）的表达组成性稳定HIF-α，但差异性促进糖酵解代谢，也发现差异性促进pVHL介导的线粒体表型。观察到线粒体形态和线粒体网络的平行变化。我们的研究揭示了pVHL在肾癌细胞中调节CHCHD 4和线粒体功能的新作用。
Dysregulated mitochondrial function is associated with the pathology of a wide range of diseases including renal disease and cancer. Thus, investigating regulators of mitochondrial function is of particular interest. Previous work has shown that the von Hippel-Lindau tumor suppressor protein (pVHL) regulates mitochondrial biogenesis and respiratory chain function. pVHL is best known as an E3-ubiquitin ligase for the α-subunit of the hypoxia inducible factor (HIF) family of dimeric transcription factors. In normoxia, pVHL recognizes and binds hydroxylated HIF-α (HIF-1α and HIF-2α), targeting it for ubiquitination and proteasomal degradation. In this way, HIF transcriptional activity is tightly controlled at the level of HIF-α protein stability. At least 80% of clear cell renal carcinomas exhibit inactivation of the VHL gene, which leads to HIF-α protein stabilization and constitutive HIF activation. Constitutive HIF activation in renal carcinoma drives tumor progression and metastasis. Reconstitution of wild-type VHL protein (pVHL) in pVHL-defective renal carcinoma cells not only suppresses HIF activation and tumor growth, but also enhances mitochondrial respiratory chain function via mechanisms that are not fully elucidated. Here, we show that pVHL regulates mitochondrial function when re-expressed in pVHL-defective 786O and RCC10 renal carcinoma cells distinct from its regulation of HIF-α. Expression of CHCHD4, a key component of the disulphide relay system (DRS) involved in mitochondrial protein import within the intermembrane space (IMS) was elevated by pVHL re-expression alongside enhanced expression of respiratory chain subunits of complex I (NDUFB10) and complex IV (mtCO-2 and COX IV). These changes correlated with increased oxygen consumption rate (OCR) and dynamic changes in glucose and glutamine metabolism. Knockdown of HIF-2α also led to increased OCR, and elevated expression of CHCHD4, NDUFB10, and COXIV in 786O cells. Expression of pVHL mutant proteins (R200W, N78S, D126N, and S183L) that constitutively stabilize HIF-α but differentially promote glycolytic metabolism, were also found to differentially promote the pVHL-mediated mitochondrial phenotype. Parallel changes in mitochondrial morphology and the mitochondrial network were observed. Our study reveals a new role for pVHL in regulating CHCHD4 and mitochondrial function in renal carcinoma cells.
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影响因子：
4.7
作者：
Hervouet, E;Demont, J;Godinot, C
通讯作者：
Godinot, C
影响因子：
15.9
作者：
Hickey, Michele M.;Lam, Jennifer C.;Simon, M. Celeste
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Simon, M. Celeste
影响因子：
5.6
作者：
Hofmann, S;Rothbauer, U;Bauer, MF
通讯作者：
Bauer, MF
影响因子：
5
作者：
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通讯作者：
Herrmann JM
影响因子：
15.9
作者：
Dirckx, Naomi;Tower, Robert J.;Maes, Christa
通讯作者：
Maes, Christa