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

线粒体质量控制是维持线粒体功能和决定细胞命运的关键，主要是通过吞噬作用来实现的。我们最近发现了一种由细胞外线粒体释放介导的另一种质量控制途径。利用线粒体毒素处理、parkin基因过表达和基因敲除的方法，我们发现线粒体应激和线粒体吞噬途径的扰动可以诱导更多的细胞外线粒体释放，这表明传统的吞丝作用的受损促使了另一种途径的出现。但具体的机制和由此产生的生物学后果仍不确定。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文库筛选实验，以确定调节有丝分裂释放的内在因素。阐明线粒体释放的生物学意义包括确定线粒体释放如何影响供体细胞和受体细胞。在分子水平和生理相关性上更好地了解这一机制，可以为治疗应用铺平道路。

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.