Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPR mt ), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPR mt  initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.