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Unravelling the role of the mitochondrial CLPXP complex in protein quality control, aging and development of Podospora anserina

揭示线粒体 CLPXP 复合物在鹅足孢菌蛋白质质量控制、衰老和发育中的作用

基本信息

批准号：
220023061
负责人：
Professor Dr. Heinz Dieter Osiewacz
金额：
--
依托单位：
Arbeitskreis Molekulare Entwicklungsbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/220023061?language=en
关键词：
Unravelling role mitochondrial CLPXP complex

项目摘要

The biological role of the mitochondrial CLPXP, a protease complex located in the mitochondrial matrix, is currently unsufficiently understood. In yeast, CLPP is missing but CLPX is implicated in a number of mitochondrial pathways (e.g. mitochondrial genome maintenance). In Caenorhabditis elegans CLPXP is involved in UPRmt, in mammals, its role in this process is controversially discussed. However, in a recent study a function of CLPP in the control of the energy metabolism related to acute myeloid leukemia was reported. In an approach towards the functional characterization of this poorly characterized protein complex, we identified a number of potential substrates and interaction partners in the fungal aging model Podospora anserina. The identified proteins strongly support a role of PaCLPXP in the control of cellular energy metabolism. Moreover, we found that ablation of PaCLPXP components results in an increased lifespan and a robust induction of autophagy. The main focus of the proposed renewal of this research project is the elucidation of the molecular mechanisms leading to autophagy induction and in particular the role of PaCLPXP in the control of this process. Based on our recent findings, we will (i) search for and characterize potential transcriptional regulators which are involved in PaCLPXP-dependent mitochondria-to-nucleus signaling and (ii) will study selected substrates and interaction partners of PaCLPXP. More specifically, we will analyze the role of candidate transcription factors identified as differentially expressed in a transcriptome analysis of the P. anserina wild type and the PaClpP deletion strain. In addition, we will study the role of PaCLPXP in controlling the cellular energy metabolism via the analysis of the activity of key enzymes and of the abundance of relevant metabolites in the wild type and PaClpXP mutants. From these investigations we expect important new exciting information about the biological function of mitochondrial CLPXP in the complex cellular network controlling cellular homeostasis that is of utmost importance for correct development and a long healthy lifespan of biological systems.

线粒体CLPXP是一种位于线粒体基质中的蛋白酶复合物，其生物学作用目前尚未得到充分了解。在酵母中，CLPP缺失，但CLPX涉及许多线粒体途径（例如线粒体基因组维持）。在秀丽隐杆线虫中，CLPXP参与UPRmt，在哺乳动物中，其在此过程中的作用有争议。然而，在最近的一项研究中，报道了CLPP在控制与急性髓性白血病相关的能量代谢中的功能。在一种方法对这种功能不佳的蛋白质复合物的表征，我们确定了一些潜在的基板和相互作用的合作伙伴在真菌老化模型柄孢鹅。所鉴定的蛋白质强烈支持PaCLPXP在控制细胞能量代谢中的作用。此外，我们发现PaCLPXP组分的消融导致寿命增加和自噬的强烈诱导。该研究项目的拟议更新的主要重点是阐明导致自噬诱导的分子机制，特别是PaCLPXP在控制这一过程中的作用。基于我们最近的研究结果，我们将（i）搜索和表征潜在的转录调节因子参与PaCLPXP依赖的细胞核信号传导和（ii）将研究选定的底物和PaCLPXP的相互作用伙伴。更具体地说，我们将分析在鹅绒委陵菜野生型和PaClpP缺失菌株的转录组分析中鉴定为差异表达的候选转录因子的作用。此外，我们将通过分析野生型和PaClpXP突变体中关键酶的活性和相关代谢产物的丰度来研究PaCLPXP在控制细胞能量代谢中的作用。从这些研究中，我们期望获得关于线粒体CLPXP在控制细胞稳态的复杂细胞网络中的生物学功能的重要的新的令人兴奋的信息，这对于生物系统的正确发育和长的健康寿命至关重要。