Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis

Several laboratories, including ours, have employed the Slc25a47tm1c(EUCOMM)Hmgu mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1, the cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses. [Display omitted] •Downregulation of WARS1 in hepatocytes triggers a hypermetabolic phenotype.•Reduced WARS1 expression leads to significant liver damage and fibrosis.•WARS1 downregulation triggers ISR and disrupts mitochondrial translation, inducing UPRmt.