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提高线粒体中生物可利用的铁水平可抑制果蝇中 PINK1 功能丧失引起的缺陷表型。

Elevating bioavailable iron levels in mitochondria suppresses the defective phenotypes caused by PINK1 loss-of-function in Drosophila melanogaster.

机构信息

Department of Laboratory Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.

Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.

出版信息

Biochem Biophys Res Commun. 2020 Nov 5;532(2):285-291. doi: 10.1016/j.bbrc.2020.08.002. Epub 2020 Aug 29.

Abstract

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, which is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron deposit was found in the SNpc of PD patients and animal models, however, the mechanisms involved in disturbed iron metabolism remain unknown. Identifying the relationship between iron metabolism and PD is important for finding new therapeutic strategies. In this study, we found that transgenic overexpression (OE) of Drosophila mitoferrin (dmfrn) or knockdown of Fer3HCH significantly mitigated the reduced mitochondrial aconitase activity, abnormal wing posture, flight deficits and mitochondrial morphology defects associated with PINK1 loss-of-function (LOF). Further work demonstrated that dmfrn OE or Fer3HCH knockdown significantly rescued the impaired mitochondrial respiration in PINK1 LOF flies, indicating that dmfrn or Fer3HCH may rescue PINK1 LOF phenotypes through elevating mitochondrial bioavailable iron levels to promote mitochondrial respiration.

摘要

帕金森病(PD)是第二常见的进行性神经退行性疾病,其特征是黑质致密部(SNpc)中的多巴胺能神经元丧失。PD 患者和动物模型的 SNpc 中发现了铁沉积,然而,涉及铁代谢紊乱的机制仍不清楚。确定铁代谢与 PD 之间的关系对于寻找新的治疗策略很重要。在这项研究中,我们发现果蝇线粒体铁蛋白(dmfrn)的转基因过表达(OE)或 Fer3HCH 的敲低显着减轻了与 PINK1 功能丧失(LOF)相关的线粒体柠檬酸合酶活性降低、异常的翅膀姿势、飞行缺陷和线粒体形态缺陷。进一步的工作表明,dmfrn OE 或 Fer3HCH 敲低显着挽救了 PINK1 LOF 果蝇中受损的线粒体呼吸作用,表明 dmfrn 或 Fer3HCH 可能通过提高线粒体生物利用铁水平来促进线粒体呼吸作用来挽救 PINK1 LOF 表型。

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