Deciphering Molecular Mechanisms of Mitochondrial Stress Response in vivo

维持线粒体的动态平衡对于广泛的信号、代谢和能量过程是必不可少的。因此，线粒体功能障碍与多种脑肌病和包括2型糖尿病、帕金森氏症和阿尔茨海默氏症在内的许多常见疾病的发展有关。作为对线粒体蛋白平衡紊乱的响应，线粒体应激反应(MSR)被启动，从而导致全局适应性转录反应，似乎部分地分享了整合应激反应(ISR)的特征。然而，这两个瀑布之间的相互联系仍然不得而知。此外，信令级联的不同步骤的确切事件顺序仍然难以捉摸。CHOP是第一个被认为在这一过程中发挥作用的转录因子(TF)，尽管由于缺乏反式激活结构域，它必须与其他转录因子异源二聚体来激活或抑制其靶基因。这项研究的总体目标是更多地阐明MSR在细胞和生物生理学中的作用，特别是CHOP在这一过程中的分子方面和体内功能。我们进一步希望确定CHOP的结合伙伴(S)，并揭示其特定的转录靶点。最后，我们想要了解ISR上游信号的性质以及MSR与内质网应激反应的相互联系。

Maintenance of mitochondrial homeostasis is essential for a broad spectrum of signalling, metabolic and energetic processes. Consequently, mitochondrial dysfunction is linked to the development of a wide range of encephalomyopathies and many common diseases including type 2 diabetes, Parkinson’s and Alzheimer’s diseases. In response to disturbed mitochondrial proteostasis, the mitochondrial stress response (MSR) is initiated, which results in global adaptive transcriptional response and seems to partially share the signature of the integrated stress response (ISR). However, the interconnection of the two cascades remains uncharted. Furthermore, the exact sequence of events for different steps of the signalling cascade remains elusive. CHOP was the first transcription factor (TF) proposed to play a role in this process, although - due to the lack of a transactivating domain - it has to heterodimerize with other TFs to activate or suppresses its target genes. The overall goal of this study is to shed more light on the role of the MSR on cellular and organismal physiology, with specific focus on the molecular aspects and in vivo functions of CHOP in this process. We further want to identify CHOP's binding partner(s) and uncover its specific transcriptional targets. Finally, we want to understand the nature of signals upstream of the ISR and the interconnection of MSR with endoplasmic reticulum stress responses.