Gene

Cell biology

Isocitrate dehydrogenase

Biology

Pyruvate dehydrogenase complex

Citric acid cycle

Citrate synthase

Epigenetics

Cell cycle

Metabolism

Biochemistry

Glyoxylate cycle

Metabolic pathway

Chromatin

Fumarase

Malate dehydrogenase

Enzyme

Mitochondrion

Aconitase

Cell

Signal Transduction and Targeted Therapy

The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.

The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry