Alexander Hooftman, Christian G Peace, Dylan G Ryan, Emily A Day, Ming Yang, Anne F McGettrick, Maureen Yin, Erica N Montano, Lihong Huo, Juliana E Toller-Kawahisa, Vincent Zecchini, Tristram A J Ryan, Alfonso Bolado-Carrancio, Alva M Casey, Hiran A Prag, Ana S H Costa, Gabriela De Los Santos, Mariko Ishimori, Daniel J Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Von Kriegsheim, Michael P Murphy, Caroline Jefferies, Christian Frezza, Luke A J O'Neill
Metabolic rewiring underlies the effector functions of macrophages1-3 , but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels...
March 8, 2023: Nature