Numb Depletion Promotes Drp1-Mediated Mitochondrial Fission and Exacerbates Mitochondrial Fragmentation and Dysfunction in Acute Kidney Injury
Numb Depletion Promotes Drp1-Mediated Mitochondrial Fission and Exacerbates Mitochondrial Fragmentation and Dysfunction in Acute Kidney Injury
复制标题
麻木耗竭促进 Drp1 介导的线粒体裂变并加剧急性肾损伤中的线粒体碎片和功能障碍
DOI：
10.1089/ars.2017.7432
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发表时间：
2018-07-25
影响因子：
6.6
通讯作者：
Nie, Jing
中科院分区：
文献类型：
--
作者：
Liu, Ze;Li, Hao;Nie, Jing
目的：线粒体断裂是急性肾损伤（阿基）过程中肾小管细胞凋亡的重要机制。然而，在阿基期间调节线粒体动力学的机制仍不清楚。Numb是在肾小管中表达的多功能衔接蛋白。本研究的目的是评估Numb在阿基.Results过程中线粒体功能障碍中的作用：缺血再灌注和顺铂诱导的阿基中Numb的表达均上调。近端小管Numb的消耗（PT-Nb-KO）使阿基恶化，表现为比野生型小鼠更严重的肾小管损伤和更高的血清肌酐。单独的Numb耗竭显著增加线粒体碎片化而不改变线粒体质量和功能，包括三磷酸腺苷产生、线粒体膜电位、氧消耗和活性氧产生。然而，PT-Nb-KO小鼠中顺铂暴露后，线粒体断裂和功能障碍显著加重。从机制上讲，Numb缺失通过增加Drp 1丝氨酸656残基（人Drp 1 ser（637））的磷酸化，触发了动力蛋白相关蛋白1（Drp 1）向线粒体的募集。Y-27632抑制Rho相关的卷曲螺旋蛋白激酶（ROCK）的活性，减弱了Nomb缺陷细胞中Drp 1 ser（656）的磷酸化和线粒体片段化。管理mdivi-1，Drp 1的药理学抑制剂，恢复线粒体形态，减弱顺铂诱导的肾小管损伤，和肾功能不全PT-Nb-KO mice.Innovation and Conclusion：我们的数据表明，Numb耗竭促进线粒体片段化，通过促进Drp 1 Ser（637）的磷酸化，从而加剧顺铂诱导的线粒体功能障碍和肾小管细胞凋亡。这些发现为阿基期间线粒体动力学的调节机制提供了新的见解。抗氧化剂。氧化还原信号。00，000-000。
Aims: Mitochondrial fragmentation is a crucial mechanism contributing to tubular cell apoptosis during acute kidney injury (AKI). However, the mechanism of modulating mitochondrial dynamics during AKI remains unclear. Numb is a multifunction adaptor protein that is expressed in renal tubules. The aim of the present study was to evaluate the role of Numb in mitochondrial dysfunction during AKI.Results: The expression of Numb was upregulated in both ischemia-reperfusion- and cisplatin-induced AKI. Depletion of Numb from proximal tubules (PT-Nb-KO) exacerbated AKI shown as more severe renal tubular damage and higher serum creatinine than wild-type mice. Numb depletion alone significantly increased mitochondrial fragmentation without altering mitochondrial mass and function, including adenosine triphosphate production, mitochondrial membrane potential, oxygen consumption, and reactive oxygen species production. However, mitochondrial fragmentation and dysfunction were significantly aggravated after cisplatin exposure in PT-Nb-KO mice. Mechanistically, Numb depletion triggered dynamin-related protein 1 (Drp1) recruitment to mitochondria by increasing the phosphorylation of Drp1 at serine 656 residue (human Drp1 ser(637)). Inhibiting the activity of Rho-associated coiled-coil containing protein kinase (ROCK) by Y-27632 attenuated phosphorylation of Drp1 ser(656) and mitochondrial fragmentation in Numb-deficient cells. Administration of mdivi-1, a pharmacological inhibitor of Drp1, restored mitochondrial morphology, attenuated cisplatin-induced tubular injury, and renal dysfunction in PT-Nb-KO mice.Innovation and Conclusion: Our data suggest that Numb depletion promotes mitochondrial fragmentation by promoting the phosphorylation of Drp1 Ser(637) and thus exacerbates cisplatin-induced mitochondrial dysfunction and tubular cell apoptosis. These findings add a novel insight into modulating mechanism of mitochondrial dynamics during AKI. Antioxid. Redox Signal. 00, 000-000.