BioProject

Several mitochondrial genetic variants have been associated with different chronic inflammatory diseases. More...

Several mitochondrial genetic variants have been associated with different chronic inflammatory diseases. However, experimental proof for the pathogenic relevance of these associations is still missing. We have reported that polymorphisms in the mitochondrial gene MT-ATP8, which encodes a subunit of the mitochondrial ATP synthase, are associated with the autoimmune skin disease bullous pemphigoid. Using a mouse model for this disease, we show here that a SNP in mt-Atp8 determine the severity of autoantibody-induced skin inflammation by modulating T effector cell function and shifting the levels of short chain fatty acids. With respect to the latter, increased levels of propionate are associated with milder disease, and systemic administration of propionate ameliorates disease. By employing the Aldara™-induced psoriasiform dermatitis model, we further demonstrate that the immunomodulatory effects of mt-Atp8 variants are also relevant for autoinflammation. Collectively, our results highlight discrete mitochondrial genetic variants as significant general modulators of skin inflammation and possibly of other organs. Overall design: Microarray analysis of total RNA prepared from liver samples obtained from four B6 Wildtype and four B6-mtFVB mice. The conplastic mouse strain, C57BL/6J-mtFVB/NJ (B6-mtFVB), was previously generated (Yu et al., 2009) and was continuously backcrossed for over 25 generations to have WT nuclear geome and a mitochondrial C57BL/6J mt-Atp8 variant (m.7778G>T). WT mice were purchased from Jackson laboratory (Bar Harbor, ME, USA). Less...