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

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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.