TCF7/MiR-802-5p promotes delayed graft function in cold-storage kidney transplantation by inducing mitochondrial stress.

Cold storage and reperfusion cause acute tubular injury and delayed graft function (DGF), but how these stresses trigger mitochondrial collapse is unclear. Here we identify a Dicer-dependent microRNA program in renal tubules, centered on miR-802-5p, that links cold-storage associated kidney transplantation (CST) to loss of mitochondrial integrity. In a CST mouse model, Dicer deletion in tubules preserved mitochondrial ultrastructure, reduced tubular injury and improved graft function. miRNA profiling revealed miR-802-5p as a Dicer-processed miRNA induced by CST that is required to abolish the protection conferred by Dicer loss. miR-802-5p directly targets the 3' UTR of IMMT (mitofilin), a core organizer of mitochondrial cristae, reducing IMMT expression, disrupting cristae structure and impairing respiration, whereas IMMT overexpression restores mitochondrial function and mitigates graft injury. Upstream, the Wnt effector TCF7 binds the miR-802 promoter and activates miR-802-5p transcription; TCF7 inhibition blunts miR-802-5p induction and protects against CST-induced damage. In kidney-transplant recipients, urinary and intrarenal miR-802-5p levels are increased in DGF and correlate with impaired graft function. Thus, a TCF7-Dicer-miR-802-IMMT axis couples CST to mitochondrial stress and represents a potential diagnostic and therapeutic target.