在人体组织器官（特别是脑）衰老的过程中，为细胞提供直接能量的线粒体损伤不断积累，这与衰老及退行性疾病加速发生密切相关。利用衰老相关疾病模型，如额颞叶变性病FTLD等认知功能障碍和肌萎缩侧索硬化症ALS等运动神经元疾病，研究脑衰老向退行性病变的发生及发展的分子、细胞基础，可揭示线粒体损伤积累导致神经退行性疾病的致病机理。根据前期工作基础，本研究以基因突变导致FTLD和ALS等疾病、且定位于线粒体嵴并与TDP-43相互作用的CHCHD10为目标分子，通过分子生物学、生化检测、免疫荧光/电镜、结构光照明超分辨成像等多学科交叉方法，研究其在线粒体形态结构和功能调控中的作用，结合建立iPSC细胞模型和果蝇动物模型进行表型分析和遗传学筛选，确定CHCHD10的功能，从分子水平、细胞水平、动物模型三个层面，阐释CHCHD10在脑衰老及神经退行性病变中的分子机制，为疾病的诊断和治疗提供理论依据。

In the research of brain and neurodegenerative diseases, accumulating evidence has suggested a causative link between mitochondrial dysfunction and accelerated degeneration associated with aging. We propose to use our established Utilizing disease models of brain aging, such as frontotemporal lobar degeneration (FTLD; aka frontotemporal dementia, FTD) for cognitive impairments and amyotrophic lateral sclerosis (ALS) for motor neuron diseases, studying of the molecular and cellular basis from aging to degeneration will help us understand the mechanism of neurodegenerative diseases resulted from mitochondrial damage. Based on our preliminary study, CHCHD10 (coiled-coil-helix-coiled-coil-helix domain 10) protein which is localized to mitochondrial cristea and its genetic mutations cause FTLD and ALS, is a TDP-43 interacting protein. We plan to employ combined multi-disciplinary approaches, such as molecular biology, biochemical assay, immune-fluorescence and immune-electronic microscopy (IEM) as well as super-resolution structured illumination microscopy (SIM), to study the role of CHCHD10 in maintenance of mitochondrial morphology and function. After establishing a couple of the cellular models (including cell lines, murine primary cortical neurons and iPSC derived neurons) and transgenic fly models, we plan to identify CHCHD10 interacting proteins, examine the defect of disease-causing mutations of CHCHD10, and finally dissect the role of CHCHD10 in aging and pathogenesis of FTLD and ALS. This study will provide new insights into common pathogenic mechanisms underlying a range of neurodegenerative diseases associated with mitochondrial dysfunctions and information useful for future development of diagnostic and therapeutic tools for these devastating aging-related diseases.