PDF(Pubmed)
Abstract：
Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.
摘要：
线粒体相关的神经退行性疾病与初级纤毛功能的破坏有关。已在Leigh综合征中发现内源性线粒体复合物I成分NDUFAFF2的突变，严重的遗传性线粒体病.ARMC9中的突变，编码一种基础体蛋白，因为Joubert综合征,大脑有缺陷的纤毛病，肾,和眼睛。这里,我们报道了线粒体代谢和初级纤毛信号之间的机制联系。我们发现NDUFAF2的丢失在体外和体内引起线粒体和纤毛缺陷，并将NDUFAF2鉴定为ARMC9的结合伴侣。我们还发现，NDUFAFF2对于纤毛形成既必要又足够，并且NDUFAFF2的外源表达挽救了已知ARMC9缺乏症患者细胞中观察到的纤毛和线粒体缺陷。补充NAD可恢复ARMC9缺陷细胞和斑马鱼的线粒体和纤毛功能障碍，并改善ARMC9缺陷患者的眼运动和运动缺陷。目前的结果提供了一个令人信服的机械联系，在人类研究的证据支持下，在初级纤毛和线粒体信号之间。重要的是,我们的发现对于针对纤毛病变的治疗方法的发展具有重要意义.
