Julia Brunner

The tricarboxylic acid (TCA) cycle is a central metabolic pathway that oxidizes nutrients to produce reducing equivalents that power oxidative phosphorylation. Nevertheless, whether TCA cycle activity supports cell fitness by regulating levels of metabolites beyond ATP is not well understood. Here, we demonstrate that citrate clearance is an essential function of the canonical TCA cycle. We show that flux through the canonical TCA cycle is increased under metabolic conditions that induce citrate accumulation. Citrate accumulation is necessary and sufficient to induce the integrated stress response (ISR) and dependence upon aconitase 2 (ACO2), the enzyme that catabolizes citrate in the TCA cycle. In vivo, ACO2 deficiency leads to citrate accumulation and triggers tubular degeneration in the kidney, a tissue unique in its ability to take up circulating citrate. Together, these results reveal that intracellular citrate accumulation can be a metabolic liability and that citrate clearance is a major function of ACO2 as an essential component of the canonical TCA cycle.

Julia Brunner is a former HFSP long-term fellow and current Kravis-WiSE fellow in the laboratory of Lydia Finley at Memorial Sloan Kettering Cancer Center in New York. Her research focuses on how metabolic networks reconfigure to support cell fate changes and cellular identity. Julia earned her Ph.D. in Immunology in 2020 under the mentorship of Gernot Schabbauer at the Medical University in Vienna where she investigated how the metabolic environment influences macrophage function in health and disease.