Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues

Marlous Kamp, Jakub Surmacki, Marc Segarra Mondejar, Tim Young, Karolina Chrabaszcz, Fadwa Joud, Vincent Zecchini, Alyson Speed, Christian Frezza () and Sarah E. Bohndiek ()
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Marlous Kamp: University of Cambridge
Jakub Surmacki: Laboratory of Laser Molecular Spectroscopy
Marc Segarra Mondejar: University of Cambridge, Biomedical Campus
Tim Young: University of Cambridge, Biomedical Campus
Karolina Chrabaszcz: Department of Experimental Physics of Complex Systems
Fadwa Joud: Robinson Way
Vincent Zecchini: University of Cambridge, Biomedical Campus
Alyson Speed: University of Cambridge, Biomedical Campus
Christian Frezza: University of Cambridge, Biomedical Campus
Sarah E. Bohndiek: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Aberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.

Date: 2024
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DOI: 10.1038/s41467-024-49403-w

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