Wars1 loss-of-function in the liver identifies a unique cytosol-to-mitochondria stress response.

Several laboratories, including ours, have used the Slc25a47tm1c(EUCOMM)Hmgu mouse model to characterize the role of SLC25A47, an hepatocyte-specific mitochondrial carrier, in hepatic metabolism and systemic physiology. In this study, we report that the hepatic and systemic phenotypes observed in Slc25a47tm1c(EUCOMM)Hmgu mouse model upon recombination of the Slc25a47-Wars1 locus, are driven by the unanticipated downregulation of Wars1, the cytosolic tryptophan aminoacyl-tRNA synthetase whose gene is located in close vicinity to Slc25a47. We show that downregulation of Wars1 in hepatocytes not only impacts on cytosolic translation, as expected, but also impairs the ability of hepatic mitochondria to translate proteins eventually leading to a profound activation of the mitochondrial unfolded protein response (UPRmt), an integral part of the mitochondrial stress response (MSR). Our results clarify the respective roles of Slc25a47 and Wars1 in both systemic and hepatic metabolism and suggest that a bidirectional stress communication system operates in the mammalian liver between the cytosol and mitochondria highlighting the complexity and promiscuity of cellular stress mechanisms. This newly identified anterograde pathway complements the previously recognized Mitochondrial-to-Cytosolic Stress Response (MCSR), which we propose to call the Cytosolic-to-Mitochondrial Stress Response (CMSR). Overall design: Slc25a47-Wars1lox/lox mice were injected with AAV8_hAAT_Cre to induce the recombination of the locus. These mice were co-injected with Slc25a47 or Wars1 to validate which gene was the main driver of the observed phenotypes upon locus recombination. Control mice for Cre were co-injected with Gfp while mice not undergoing recombination were injected with Gfp alone. The viruses were under the hAAT promoter, therefore the recombination is specifically targeted to hepatocytes. Each condition was replicated in 6 mice.