細胞外ミトコンドリア放出による生体恒常性維持と加齢・疾患の関連について

关于细胞外线粒体释放维持生物稳态与衰老和疾病之间的关系

• 批准号: 21K15627
• 负责人: 鐘 其静
• 金额: $ 3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-02-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K15627/
• 关键词: Mitochondria; Extracellular release; Mitophagy; ミトコンドリア; 細胞外放出; マイトファジー

Mitochondrial quality control, which is crucial for maintaining mitochondrial function and cell fate determination, is mainly achieved through mitophagy. We recently discovered an alternative quality control pathway mediated by extracellular mitochondria release. Using mitochondrialtoxin treatment and parkin gene overexpression and knockdown approaches, we found that mitochondrial stress and perturbation of mitophagy pathway induce greater extracellular mitochondria release, suggesting that impairment of conventional mitophagy prompts alternative pathway.However, the detailed mechanisms and the resulting biological consequences remain indefinite. Here I propose to study the mechanisms ofmitochondria secretion and its cell-autonomous and non-cell autonomous biological consequences. Briefly, the study of mechanisms involves CRISPR library screening assay to identify intrinsic factors that regulate mitovesicle release. Elucidation of the biological significance of mitochondria release includes determination on how mitochondria release affects the donor and recipient cells. A better understanding of themachinery at molecular level and physiological relevance can pave the way for therapeutic implication.

线粒体质量控制对于维持线粒体功能和细胞命运确定至关重要，主要是通过线粒体实现的。我们最近发现了一个由细胞外线粒体释放介导的替代质量控制途径。使用线粒体毒素治疗和Parkin基因过表达和敲低方法，我们发现线粒体应力和线粒体途径的扰动会诱导更大的细胞外线粒体释放，这表明传统的线粒体促进途径受损会损害传统的替代途径。在这里，我建议研究蒙蒙软糖分泌的机理及其细胞自主和非细胞自主生物学后果。简而言之，对机制的研究涉及CRISPR库筛选测定法，以识别调节释放Mitovesicle的内在因素。线粒体释放的生物学意义的阐明包括对线粒体释放如何影响供体和受体细胞的确定。更好地理解分子水平和生理相关性的神经学可以为治疗意义铺平道路。