Abstract
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 (UPRmt), 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 UPRmt 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.
Highlights
Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans
Reduction in mitochondrial proteins import, and accumulation of mitochondrial protein precursors in the cytosol, induces the unfolded protein response activated by mistargeting of proteins ( UPRam), which promotes the activity of the proteasome[7]
While attenuation of protein translation was clearly shown to be dependent on the CHOP/ATF4/ ATF5 axis of the U PRmt[1,13] the activation of cytosolic heat shock proteins and the elimination of toxic proteins aggregates were found to be independent of this a xis[3], suggesting that different axes of the U PRmt may regulate distinct aspects of cytosolic proteostasis
Summary
The observation that protein aggregates are observed in several neurodegenerative diseases suggest that defect in proteostasis is especially toxic to the nervous system. We found a significant activation of 2 out of 4 markers (phospho- ERα, phosphoAkt) was observed in both males and females treated with doxycycline alone, and activation of all 4 makers of this axis was observed when doxycycline was combined with heat shock (Fig. 2G–I). These results suggest that the ERα-mediated activation of the proteasome may play a role in the reduction in K48Ub-linked proteins upon treatment with doxycycline, with and without heat shock. Increased cAMP levels as a result of growth factor stimulation or fasting have been reported to lead to increased proteasome subunit phosphorylation and subsequent increased proteasome activity mediated by PKA in muscle and liver[31], while other groups have observed that increased cAMP levels as a result of inhibiting cAMP-phosphodiesterase activity with Isobutylmethylxanthine (IBMX) suppressed proteasome a ctivity[30,32]
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