miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation

Background Kidney injury due to cold storage-associated transplantation (CST) is amajor factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. Methods The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti-microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR- 147 in CST injury in mouse and renal tubular cell models. Results Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti-miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro. Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147-induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. Conclusions microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.

Automated summary

This study reveals the pathogenic role of microRNAs, particularly miR-147, in CST injury and graft dysfunction. MiR-147 induces mitochondrial damage and renal tubular cell death by repressing NDUFA4. These findings highlight miR-147 and NDUFA4 as potential therapeutic targets in kidney transplantation.