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Bresciani 2022 J Hepatol

From Bioblast
Publications in the MiPMap
Bresciani N, Demagny H, Lemos V, Pontanari F, Li X, Sun Y, Li H, Perino A, Auwerx J, Schoonjans K (2022) The Slc25a47 locus is a novel determinant of hepatic mitochondrial function implicated in liver fibrosis.

ยป J Hepatol 77:1071-82. PMID: 35714811 Open Access

Bresciani Nadia,  Demagny Hadrien,  Lemos Vera,  Pontanari Francesca,  Li Xiaoxu,  Sun Yu,  Li Hao,  Perino Alessia,  Auwerx Johan,  Schoonjans Kristina (2022) J Hepatol

Abstract: 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.

We used a murine loss-of-function model to unravel the role of this transporter in mitochondrial and hepatic homeostasis. We performed extensive metabolic phenotyping and molecular characterization of newly generated Slc25a47hep-/- and Slc25a47-Fgf21hep-/- mice.

Slc25a47hep-/- mice displayed a wide variety of metabolic abnormalities, as a result of sustained energy deficiency in the liver originating from impaired mitochondrial respiration. This mitochondrial phenotype was associated with an activation of the mitochondrial stress response (MSR) in the liver, and the development of fibrosis, which was exacerbated upon feeding a high-fat high-sucrose diet. The MSR induced the secretion of several mitokines, amongst which FGF21 played a preponderant role on systemic physiology. To dissect the FGF21-dependent and -independent physiological changes induced in Slc25a47hep-/- mice, we generated a double Slc25a47-Fgf21hep-/- mouse model and demonstrated that several aspects of the hypermetabolic state were driven by hepatic secretion of FGF21. On the other hand, the metabolic fuel inflexibility observed in Slc25a47hep-/- mice could not be rescued with the genetic removal of Fgf21.

Collectively, our data place the Slc25a47 locus at the center of mitochondrial homeostasis, which upon dysfunction triggers robust liver-specific and systemic adaptive stress responses. The prominent role of the Slc25a47 locus in hepatic fibrosis identifies this carrier, or its transported metabolite, as a potential target for therapeutic intervention. โ€ข Keywords: FGF21, Fibrosis, Liver, Metabolism, Mitochondrial Solute Carriers, Mitochondrial Stress Response โ€ข Bioblast editor: Plangger M โ€ข O2k-Network Lab: CH Lausanne Auwerx J

Labels: MiParea: Respiration, mt-Membrane, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Regulation: Ion;substrate transport  Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, S, NS, ROX  HRR: Oxygraph-2k