The Slc25a47 locus is a novel determinant of hepatic mitochondrial function implicated in liver fibrosis

Background & Aims: Transporters of the SLC25 mitochondrial carrier superfamily bridge cytoplasmic and mitochondrial metabolism by channeling metabolites across mitochondrial membranes and are pivotal for metabolic homeostasis. Despite their physiological relevance as gatekeepers of cellular metabolism, most of the SLC25 family members remain uncharacterized. We undertook a comprehensive tissue distribution analysis of all Slc25 family members across metabolic organs and identified SLC25A47 as a liver-specific mitochondrial carrier. Method: We used a murine loss-of-function (LOF) model to unravel the role of this transporter in mitochondrial and hepatic homeostasis. We performed extensive metabolic phenotyping and molecular characterization of Slc25a47hep-/- mice. Results: Slc25a47hep-/- mice displayed a wide variety of metabolic abnormalities, as a result of sustained energy deficiency in the liver originating from impaired mitochondrial respiration in this organ. This mitochondrial phenotype was associated with a robust activation of the mitochondrial stress response in the liver, which in turn, induced the secretion of several mitokines, amongst which FGF21 played a preponderant role in the translation of the effects of the MSR on systemic physiology. To dissect the FGF21-dependent and -independent physiological changes induced by the loss of Slc25a47, we generated a double Slc25a47-Fgf21 LOF mouse model, and demonstrated that several aspects of the hypermetabolic state was entirely driven by hepatic secretion of FGF21. On the other hand, the metabolic fuel inflexibility induced by loss of Slc25a47 could not be rescued by genetical removal of Fgf21. Conclusion: Collectively, our data place SLC25A47 at the center of mitochondrial homeostasis, which upon dysfunction triggers robust liver-specific and systemic adaptive stress responses. Hepatic mRNA profiles of 9 week- old- Slc25a47hep-/- and Slc25a47hep+/+ mice