Abstract

Cytosolic citrate is imported from the mitochondria by SLC25A1, and from the extracellular milieu by SLC13A5. In the cytosol, citrate is used by ACLY to generate acetyl-CoA, which can then be exported to the endoplasmic reticulum (ER) by SLC33A1. Here, we report the generation of mice with systemic overexpression (sTg) of SLC25A1 or SLC13A5. Both animals displayed increased cytosolic levels of citrate and acetyl-CoA; however, SLC13A5 sTg mice developed a progeria-like phenotype with premature death, while SLC25A1 sTg mice did not. Analysis of the metabolic profile revealed widespread differences. Furthermore, SLC13A5 sTg mice displayed increased engagement of the ER acetylation machinery through SLC33A1, while SLC25A1 sTg mice did not. In conclusion, our findings point to different biological responses to SLC13A5- or SLC25A1-mediated import of citrate and suggest that the directionality of the citrate/acetyl-CoA pathway can transduce different signals.

Directionality of the citrate/acetyl-CoA pathway transduce different signals is shown in mice overexpressing citrate transporters, SLC25A1 or SLC13A5.

Details

Title
The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse
Author
Fernandez-Fuente, Gonzalo 1   VIAFID ORCID Logo  ; Overmyer, Katherine A. 2 ; Lawton, Alexis J. 3   VIAFID ORCID Logo  ; Kasza, Ildiko 4 ; Shapiro, Samantha L. 1 ; Gallego-Muñoz, Patricia 5 ; Coon, Joshua J. 6   VIAFID ORCID Logo  ; Denu, John M. 3 ; Alexander, Caroline M. 4 ; Puglielli, Luigi 7   VIAFID ORCID Logo 

1  University of Wisconsin-Madison, Department of Medicine, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin-Madison, Waisman Center, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
2  University of Wisconsin-Madison, Department of Biomolecular Chemistry, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); Morgridge Institute for Research, Madison, USA (GRID:grid.509573.d) (ISNI:0000 0004 0405 0937) 
3  University of Wisconsin-Madison, Department of Biomolecular Chemistry, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin-Madison, Wisconsin Institute for Discovery, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
4  University of Wisconsin-Madison, McArdle Laboratory for Cancer Research, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
5  University of Valladolid, Department of Cell Biology, Genetics, Histology and Pharmacology, Faculty of Medicine, Valladolid, Spain (GRID:grid.5239.d) (ISNI:0000 0001 2286 5329) 
6  University of Wisconsin-Madison, Department of Biomolecular Chemistry, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); Morgridge Institute for Research, Madison, USA (GRID:grid.509573.d) (ISNI:0000 0004 0405 0937); University of Wisconsin-Madison, Department of Chemistry, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
7  University of Wisconsin-Madison, Department of Medicine, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin-Madison, Waisman Center, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); Veterans Affairs Medical Center, Geriatric Research Education Clinical Center, Madison, USA (GRID:grid.511190.d) (ISNI:0000 0004 7648 112X); University of Wisconsin-Madison, Department of Neuroscience, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
Pages
926
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-023-05311-1
ProQuest document ID
2862851331
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.