Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect

Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca²⁺-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.