miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney
Jiefu Zhu1,2,3, Xiaohong Xiang3,4, Xiaoru Hu3,5
1Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
Significance Statement:
Cold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.
Background:
Kidney injury due to cold storage-associated transplantation (CST) is a major 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.
Insights
MicroRNA-147 (miR-147) exacerbates cold storage-associated transplantation (CST) injury by targeting NDUFA4, leading to kidney damage. Blocking miR-147 or boosting NDUFA4 offers potential therapeutic strategies for kidney transplantation.
Area of Science:
- Renal transplantation research
- Molecular biology of microRNAs
- Organ preservation injury
Background:
- Cold storage-associated transplantation (CST) injury significantly impacts renal transplant outcomes.
- The precise role and regulatory mechanisms of microRNAs in CST injury are not well understood.
Purpose of the Study:
- To investigate the role of microRNAs in cold storage-associated transplantation (CST) injury.
- To identify specific microRNAs and their targets involved in CST pathogenesis.
- To explore potential therapeutic targets for mitigating CST injury in kidney transplantation.
Main Methods:
- Utilized proximal tubule Dicer knockout mice to assess microRNA function in CST.
- Employed small RNA sequencing to profile microRNA expression changes post-CST.
- Investigated the role of microRNA-147 (miR-147) using anti-miR-147 and miR-147 mimics in vitro and in vivo.
Main Results:
- Dicer knockout in proximal tubules reduced CST kidney injury.
- miR-147 was consistently upregulated in mouse and human kidney grafts experiencing CST.
- miR-147 targets NDUFA4, a mitochondrial complex component, inducing cell death; NDUFA4 overexpression protected against injury.
Conclusions:
- MicroRNAs, particularly miR-147, play a pathogenic role in CST injury and graft dysfunction.
- miR-147-induced NDUFA4 repression leads to mitochondrial damage and renal tubular cell death.
- miR-147 and NDUFA4 represent promising therapeutic targets for improving kidney transplant outcomes.
