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，这是至关重要的维持线粒体功能和细胞命运的决定，主要是通过线粒体自噬实现。我们最近发现了一个替代的质量控制途径介导的细胞外线粒体释放。我们利用线粒体毒素处理和parkin基因过表达及敲低的方法，发现线粒体应激和线粒体自噬途径的干扰可诱导细胞外线粒体释放增加，提示常规线粒体自噬途径的损伤促进了替代途径的产生，但具体机制和由此产生的生物学后果仍不明确。在这里，我建议研究线粒体分泌的机制及其细胞自主和非细胞自主的生物学后果。简而言之，机制的研究涉及CRISPR文库筛选测定以鉴定调节线粒体囊泡释放的内在因子。线粒体释放的生物学意义的阐明包括确定线粒体释放如何影响供体和受体细胞。在分子水平和生理相关性上更好地理解这种机制可以为治疗意义铺平道路。