Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle
Summary
The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme t
Content
# Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle
*Published: 2026 Apr 30*
The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the
generation of reducing equivalents that power oxidative phosphorylation.
Nevertheless, the requirement for components of the TCA cycle is
context-specific, raising the question of which TCA cycle outputs support cell
fitness. Here, we demonstrate that citrate clearance is an essential function of
the TCA cycle. As citrate production increases, so do TCA cycle activity and
dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism
in the TCA cycle. Disrupting citrate catabolism activates the integrated stress
response and impairs cell fitness, and these effects are reversed by preventing
citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2
deficiency induces citrate accumulation and triggers tubular degeneration in the
kidney, a tissue that physiologically takes up circulating citrate. Thus,
intracellular citrate accumulation can be a metabolic liability, and citrate
clearance is a major function of ACO2 in the TCA cycle.
DOI: 10.1016/j.cell.2026.01.028