Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

Abstract

Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.

Research progress on ncRNAs regulation of mitochondrial dynamics in diabetes

“…There is an increasing number of studies have demonstrated the potential mechanisms of ncRNA-regulated mitochondrial dynamics. Chen et al, 2015;Costa et al, 2013;Yoon et al, 2021). Thus, further research is warranted on the role of ncRNAs as a putative therapeutic target in the treatment of diabetes and its complications.…”

“…Thus, it is worth investigating the participation of mitophagy in diabetes and its complications and the possibility of mitophagy as a potential therapeutic target. Finally, previous research on miRNA pharmacogenomics has demonstrated that miRNAs can affect the efficacy of the drug via downregulating gene expression that is essential for drug functions (S. M. Chen et al, 2015; Costa et al, 2013; Yoon et al, 2021). Thus, further research is warranted on the role of ncRNAs as a putative therapeutic target in the treatment of diabetes and its complications.…”

“…As suggested by Yoon et al (2021) renal mitochondrial dynamics and mitophagy disorders were observed in the renal cortex of chronic kidney disease (CKD) mice. However, both the mitochondrial dynamics and miR-4516 and PTEN-induced putative kinase protein 1/Parkinmediated mitophagy disorder could be improved by melatonin-induced miR-4516 (Yoon et al, 2021).…”

“…As suggested by Yoon et al (2021) renal mitochondrial dynamics and mitophagy disorders were observed in the renal cortex of chronic kidney disease (CKD) mice. However, both the mitochondrial dynamics and miR-4516 and PTEN-induced putative kinase protein 1/Parkinmediated mitophagy disorder could be improved by melatonin-induced miR-4516 (Yoon et al, 2021). A recent study proposed that the dysfunctional mitochondrial dynamics are closely associated with mitophagy and PM2.5-mediated mitophagy can be attenuated by miR-411, which directly targets and represses Drp1 in hepatic stellate cells (Z. J.…”

Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating tiRNAs

“…It can regulate the activity of the members of the MMP family, which is involved in remodeling the endometrium, thereby alleviating the progress of the epithelium in endometriosis 7,8 . In addition, melatonin has an antifibrotic effect in renal tissue, which improves mitochondrial homeostasis and prevents uterine horn‐induced intraperitoneal adhesion in a rat model 9,10 . Therefore, melatonin supplementation could restore the physiological function of the uterus to its normal state.…”