Imbalance of mitochondrial respiratory chain complexes in the epidermis induces severe skin inflammation. Mus musculus

Accumulation of mitochondrial DNA (mtDNA) deletions to detrimental levels in few cells and chronic inflammation are concomitant during aging in many tissues, thus raising the question of a causal link between both phenomena. To approach this, we generated mice which accumulate such deletions in the epidermis by expression of a mutant TWINKLE helicase in keratinocytes. These short-lived mice showed a severe depletion of mtDNA, as well as low amounts of large-scale deletions in the epidermis. These alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression in the epidermis. This caused a severe inflammatory phenotype, with massive immune cell infiltrates already before birth, resulting in serous scabs at the ventral skin region and limb joints. Altogether, these data suggest that severe respiratory chain dysfunction, as observed in a few cells in aged tissues, might be involved in the development of chronic inflammation. Overall design: Epidermal RNA was isolated from newborn mice expressing a mutant form of the mitochondrial helicase Twinkle (K320E-TwinkleEpi) under the control of the K14 promotor. RNA isolated from the epidermis of R26-K320E-TwinkleloxP/+ newborns was used as control. RNA was extracted and the expression profile between the genotypes was compared.