The Pathogenic Mechanism of C19orf12 in Mitochondrial Membrane Protein Associated Neurodegeneration

摘要 脑内神经退行性变伴铁蓄积(NBIA)定义了一组罕见的遗传性疾病 神经系统中铁沉积和相关神经元丢失的显著特征。虽然意义重大 遗传学研究进展揭示了线粒体功能障碍在发病机制中的重要作用 在NBIA中，线粒体异常和金属失调的潜在机制 难以捉摸。在这方面，我们重点研究了与铁积累相关的线粒体膜蛋白。 (MPAN)是由C19orf12基因突变引起的，C19orf12是一种功能未知的蛋白质。在试行阶段 研究中，我们分析了一例MPAN病例的人类活检组织、小鼠脑组织和人类神经母细胞瘤M17细胞。 用C19orf12基因敲除(KO)来探讨C19orf12在MPAN线粒体中的作用 正常的线粒体。的确，我们对MPAN脑活检的影像研究的初步数据 条件表明存活神经元中的线粒体受损，这突显了 MPAN中的线粒体功能障碍。C19orf12的体内检测显示线粒体 C19orf12在小鼠脑组织中的定位和蛋白表达重要的是，我们发现C19orf12是 与体内电子转移链的线粒体复合体IV相关。C19orf12的体外研究 C19orf12 KO M17细胞线粒体呼吸分析显示线粒体氧受损 体外消费。此外，微量金属分析显示，铁和铜在 C19orf12 KO细胞线粒体。综上所述，这些令人兴奋的数据表明， C19orf12在线粒体功能和金属调节中的生理状态及其可能的相关 C19orf12在MPAN发病机制中的作用因此，进一步的研究探索 MPAN中金属调节的机制以及C19orf12突变如何损害线粒体功能 这是正当的。目前的应用将阐明C19orf12连接的新机制 MPAN病理中的线粒体功能障碍和金属失调。

Abstract Neurodegeneration in brain with iron accumulation (NBIA) defines a group of rare hereditary diseases with prominent features of iron deposition and related neuronal loss in the nervous system. Although significant progress in the genetic studies uncovered the essential role of mitochondrial dysfunction in the pathogenesis of NBIA, the underlying mechanism of mitochondrial abnormality and metal dysregulation in NBIA remains elusive. In this regard, we focused on the mitochondrial membrane proteins associated iron accumulation (MPAN) that was caused by genetic mutations in C19orf12, a protein with unknown function. In the pilot study, we analyzed human biopsy of an MPAN case, mouse brain tissue and human neuroblastoma M17 cell lines with C19orf12 knock-out (KO) to explore the role of C19orf12 in the mitochondria of MPAN and also in the normal mitochondria. Indeed, our preliminary data of imaging investigation on brain biopsy of MPAN conditions suggested mitochondria are impaired in the surviving neurons, which underscored the mitochondrial dysfunction in MPAN. The exploration of C19orf12 in vivo showed the mitochondrial localization and protein expression of C19orf12 in mouse brain tissues. Importantly, we found that C19orf12 is associated with mitochondrial complex IV of the electron transfer chain in vivo. In vitro study of C19orf12, mitochondrial respiration analysis of C19orf12 KO M17 cells showed impaired mitochondrial oxygen consumption in vitro. Furthermore, trace metal analysis showed both iron and copper dysregulation in the mitochondria of C19orf12 KO cells. Taken together, this exciting data demonstrated that the critical role of C19orf12 in mitochondrial function and metal regulation in the physiological condition and the likely related disturbance of C19orf12 during the pathogenesis of MPAN. Therefore, the further study to explore the mechanism of metal regulation in MPAN and how C19orf12 mutants impair mitochondrial function is warranted. The current application will shed light on the novel mechanism of C19orf12 that is linking mitochondrial dysfunction and metal dysregulation in the MPAN pathology.