The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse

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.

Automated summary

In the cytosol, mitochondria and extracellular milieu can import citrate through SLC25A1 and SLC13A5. Citrate is used by ACLY to generate acetyl-CoA, which is then exported to the endoplasmic reticulum (ER) through SLC33A1. Mice with overexpression of SLC13A5 displayed a progeria-like phenotype and increased engagement of the ER acetylation machinery, while SLC25A1 overexpression did not show these phenotypes and engagement.