Distal Mitochondrial Signaling in a Multicellular Organism

描述(申请人提供)：线粒体功能障碍是几乎所有年龄起病的神经退行性疾病的主要后果，也可能是接触到范围广泛的环境毒素的轻微水平的后果。令人惊讶的是，申请人的实验室发现，一种细胞类型的线粒体应激可以传递到未经历线粒体应激的远端细胞类型。利用线虫体内的组织特异性启动子，驱动神经系统中ETC复合体IV的一个亚单位dsRNA的表达，已经证明神经元线粒体应激可以传递到远端细胞，如肠道。神经系统传递这种轻微压力的能力会延长整个动物的寿命和存活率。拟议研究的目标是确定这一信号机制的来源和性质。 与公共健康相关：我们已经发现，一个细胞的线粒体可以与远距离的细胞进行通信。这种交流是在神经系统中启动的，确保动物在应激条件下的生存。这些细胞交流的语言的识别将为患有与线粒体功能障碍相关的疾病的人提供新的治疗途径，如中风、阿尔茨海默氏症、帕金森氏症、亨廷顿氏症、糖尿病和罕见的代谢性疾病。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is a primary consequence of nearly all age-onset neurodegenerative diseases, and can be the consequence of exposure to even mild levels of a wide-range of environmental toxins. Surprisingly, the applicant's lab has uncovered that mitochondrial stress in one cell type can be communicated to a distal cell type that has not undergone mitochondrial stress. Using tissue specific promoters in the nematode C. elegans that drive expression of dsRNA of a subunit of complex IV of the ETC in the nervous system, it has been shown that neuronal mitochondrial stress can be communicated to distal cells, such as the intestine. The ability of the nervous system to communicate this mild stress results in increased longevity and survival of the entire animal. The goal of the proposed studies is to identify the source and nature of this signaling mechanism. PUBLIC HEALTH RELEVANCE: We have discovered that mitochondria from one cell can communicate to cells at a distance. This communication is initiated in the nervous system and ensures the survival of an animal under conditions of stress. The identity of the language in which these cells communicate will provide new avenues of therapy for people that suffer from diseases associated with mitochondrial malfunction, such as stroke, Alzheimer's, Parkinson's, Huntington's, diabetes and rare metabolic diseases.