Allergens of the urushiol family promote mitochondrial dysfunction by inhibiting the electron transport at the level of cytochromes b and chemically modify cytochrome c ₁

Abstract

Background

Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8 ⁺ effector T-cells and downregulated by CD4 ⁺ T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response.

Results

Electron microscopy observations of mouse ears exposed to litreol (3- n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3- n-pentadecyl-8,11,13 enyl/3- n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with ³H-litreol, indicated that this urushiol was bound to cytochrome c ₁. According to the proximity of cytochromes c ₁ and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes b _L (cyt b ₅₆₆) and b _H (cyt b ₅₆₂).

Conclusion

Our data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40659-021-00357-z.