Deciphering molecular mechanisms underlying the unconventional extracellular mitochondria release

破译非常规细胞外线粒体释放的分子机制

• 批准号: 17F17413
• 负责人: 望月 秀樹
• 金额: $ 1.41万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2017
• 资助国家: 日本
• 起止时间: 2017-11-10 至 2020-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17F17413/
• 关键词: Mitochondria; Mitophagy; Parkin; Parkinson's disease; Rotenone; mitochondria; rotenone; parkin

Selective removal of damaged mitochondria by mitophagy is crucial for maintaining mitochondrial quality control and cell viability. Here we demonstrate an alternative quality control pathway mediated by extracellular mitochondria release. We performed real time tracking of fluorescence-labelled mitochondria in cultured cells and observed release of mitochondria into extracellular space. Using mitochondrial toxin treatment and parkin gene overexpression and knockdown approaches, we found that mitochondrial stress and perturbation of mitophagy induce greater extracellular mitochondria release. Remarkably, fibroblasts and CSF from Parkinson’s disease patients carrying parkin mutations showed increased extracellular mitochondria release compared to control subjects, providing evidence in clinical context that impairment of conventional mitophagy prompts the alternative pathway.

通过线粒体自噬选择性去除受损的线粒体对于维持线粒体质量控制和细胞活力至关重要。在这里，我们证明了一种替代的质量控制途径介导的细胞外线粒体释放。我们进行了真实的时间跟踪荧光标记的线粒体在培养的细胞，并观察到线粒体释放到细胞外空间。使用线粒体毒素处理和帕金基因过表达和敲除方法，我们发现线粒体应激和线粒体自噬的干扰会诱导更多的细胞外线粒体释放。值得注意的是，与对照受试者相比，来自携带parkin突变的帕金森病患者的成纤维细胞和CSF显示出增加的细胞外线粒体释放，这在临床背景下提供了常规线粒体自噬受损促进替代途径的证据。

项目成果

Small-molecule inhibitors of p53/negative regulator-interaction protect dopaminergic neurons against MPP+/MPTP-induced neurotoxicity

p53/负调节因子相互作用的小分子抑制剂保护多巴胺能神经元免受 MPP /MPTP 诱导的神经毒性

• 发表时间: 2017
• 作者: Choong CJ;Sasaki T;Hayakawa H;Baba K;Hirata Y;Uesato S;Mochizuki H.
• 通讯作者: Mochizuki H.

Inappropriate trafficking of damaged mitochondria in Parkinson’s disease

帕金森病中受损线粒体的不当运输

• DOI: 10.21037/sci.2017.02.07
• 发表时间: 2017
• 期刊: Stem Cell Investigation
• 作者: Choong Chi-Jing;Mochizuki Hideki
• 通讯作者: Mochizuki Hideki

New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death.

新的5-芳基取代的2-氨基苯甲酰胺型HDAC抑制剂具有二季帕皮嗪组及其对缺血诱导的神经元细胞死亡的改善作用。

• DOI: 10.1038/s41598-018-19664-9
• 发表时间: 2018-01-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hirata Y;Sasaki T;Kanki H;Choong CJ;Nishiyama K;Kubo G;Hotei A;Taniguchi M;Mochizuki H;Uesato S
• 通讯作者: Uesato S