Metabolic impact of a polymorphism in the mitochondrial gene mt-Cytb on the pathogenesis of psoriasis

银屑病的病因是复杂的，推测遗传特征和环境因素、先天免疫和获得性免疫之间的多因素交互作用。最近的研究发现，在慢性炎症性疾病中，细胞代谢途径和炎症过程(免疫代谢)之间存在广泛的相互作用。线粒体在调节细胞新陈代谢中起着关键作用，因为它们是细胞能量产生和合成代谢和分解代谢过程之间转换的中心组成部分。线粒体影响许多细胞过程，并通过控制免疫细胞中的细胞代谢参与炎症过程的调节；因此，线粒体的功能与慢性炎症的发病机制有关。线粒体携带自己的基因组，线粒体DNA(MtDNA)编码氧化磷酸化系统的几个亚单位，构成细胞能量产生的关键组成部分。据报道，线粒体DNA的突变与线粒体功能障碍有关，因此这种突变会导致细胞功能障碍。事实上，线粒体复合体III的功能障碍会导致小鼠免疫细胞受损。与此同时，最近的一项研究发现，线粒体复合体III基因的一个变异与牛皮癣患者有关。因此，我们假设线粒体编码的复合体III基因突变与银屑病的病理有关。在这项研究中，我们将1)利用共生小鼠品系(C57BL/6J-mt129S1/SvlmJ)和野生型品系(C57BL/6J)，评估线粒体复合体III基因中线粒体DNA变异(mt-cytb)在银屑病模型中的影响；2)研究从C57BL/6J-mt12S1/SvlmJ和C57BL/6J小鼠中分离的致病细胞类型(即γδT细胞和树突状细胞)的细胞和线粒体功能；以及3)整合上述免疫细胞的细胞代谢和转录数据，以确定控制银屑病发病机制的分子途径的mt-cytb基因变异衍生的潜在介体。预期的发现将为牛皮癣的新治疗策略提供基础。

The etiology of psoriasis is complex, inferring multifactorial interactions between genetic traits and environmental factors, innate and adaptive immunity. Recent research efforts have uncovered extensive interaction between cellular metabolic pathways and inflammatory processes (immunometabolism) in chronic inflammatory diseases. Mitochondria play a critical role in the regulation of cellular metabolism as they are a central component of the cellular energy production and conversion between anabolic and catabolic processes. Mitochondria affect many cellular processes, and take part in the regulation of inflammatory processes by controlling cellular metabolism in immune cells; consequently, mitochondrial functions are relevant in the pathomechanisms of chronic inflammatory conditions. Mitochondria carry their own genome, mitochondrial DNA (mtDNA) encoding several subunits of the oxidative phosphorylation system, which constitutes a key component of the cellular energy production. Mutations in the mtDNA reportedly link to mitochondrial dysfunction, thus such mutations result in cellular dysfunctions. In fact, dysfunctions in mitochondrial complex III results in immune cell impairment in mice. In parallel, a recent study identified a variation in the mitochondrial complex III gene is associated with psoriasis patients. Thus, we hypothesized that mutations in mitochondrially encoded complex III gene is associated with pathology of psoriasis. In this research proposal, we will 1) evaluate the impact of the mtDNA variant in the mitochondrial complex III gene (mt-Cytb) in psoriasis disease models, using a conplastic mouse strain (C57BL/6J-mt129S1/SvlmJ) and wild-type strain (C57BL/6J), 2) investigate cellular and mitochondrial functions in disease responsible cell types (i.e., γδT cells and dendritic cells) isolated from C57BL/6J-mt129S1/SvlmJ and C57BL/6J mice, and 3) integrate cellular metabolomics and transcriptomics data of the aforementioned immune cells to identify the mt-Cytb gene variant-derived potential mediators that control the molecular pathways involved in psoriasis pathogenesis. The expected findings will provide a basis for a novel therapeutic strategy for psoriasis.