Title: The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse.
Legend: (a) Schematic view of the citrate/acetyl-CoA pathway. Image was generated using BioRender. (b) SLC13A5 sTg and SLC25A1 sTg mice were generated with an inducible Tet-Off expression system under the control of the Rosa26 locus for systemic overexpression. (c) SLC25A1 sTg mouse and WT littermate when 75 days old. (d) SLC13A5 sTg mice were studied under 3 different experimental conditions based on the starting point of overexpression: overexpression from conception (OC), overexpression from birth (OB), and overexpression from weaning (OW). (e) SLC13A5 sTgOC mice and WT littermate at birth. (f) Representative SLC13A5 sTgOW, SLC13A5 sTgOB, and WT littermates when 125 days old. (g) Body weight of male and female WT, SLC13A5 sTgOB, and SLC13A5 sTgOW (n=20/group). #P<0.0005 via mean comparison using Student’s t-test. (h) Body weight of male and female WT and SLC25A1 sTg animals (n=20/group). **P<0.005 via mean comparison using Student’s t-test. (i) Lifespan of WT, SLC25A1 sTg, SLC13A5 sTgOW and SLC13A5 sTgOB mice (n=25/group). Maximum lifespan of SLC13A5 sTgOB mice: males = 175 days, females = 147 days; P < 0.0005 via Kaplan-Meier lifespan test. (j) Representative Western blots showing SLC13A5 and SLC25A1 overexpression in different tissues (1, WT mice; 2, sTg mice). (k) Total protein quantification of different tissues from SLC13A5 and SLC25A1 sTg mice displayed as fold of change vs WT animals (n=12/group). *P<0.05, **P<0.005, #P<0.0005 via mean comparison using Student’s t-test.
Citation: Fernandez-Fuente, G., Overmyer, K. A., Lawton, A. J., Kasza, I., Shapiro, S. L., Gallego-Muñoz, P., Coon, J. J., Denu, J. M., Alexander, C. M., & Puglielli, L. (2023). The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse. Communications biology, 6(1), 926. https://doi.org/10.1038/s42003-023-05311-1
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.
Investigator: Luigi Puglielli, MD, PhD
About the Lab: The Puglielli Lab’s research interests focus on molecular mechanisms of neurodevelopment and neurodegeneration. The laboratory employs a combination of biochemical, cellular, molecular, and genetic approaches in in vitro, ex vivo and in vivo models.