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Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis
Yeo Min Yoon1, Gyeongyun Go2,3, Sungtae Yoon4
1Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea.
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.
Insights
Melatonin treatment restores mitophagy in chronic kidney disease (CKD) by regulating the miR-4516/SIAH3 pathway, improving mitochondrial function and attenuating kidney fibrosis.
Area of Science:
- Cell Biology
- Renal Physiology
- Molecular Medicine
Background:
- Mitophagy, a selective form of autophagy, is crucial for mitochondrial quality control.
- Dysfunctional mitophagy contributes to renal fibrosis and chronic kidney disease (CKD) progression.
- The precise molecular mechanisms underlying mitophagy loss in CKD are not fully understood.
Purpose of the Study:
- To investigate the role of miR-4516 and its target SIAH3 in CKD-associated mitophagy.
- To explore the therapeutic potential of melatonin in modulating mitophagy and treating CKD.
- To elucidate the miR-4516/SIAH3/PINK1 mitophagy signaling axis in CKD.
Main Methods:
- Analysis of miR-4516 and SIAH3 expression in renal cortex of CKD mice.
- Administration of melatonin to CKD mice.
- Assessment of mitophagy markers (PINK1/Parkin) and mitochondrial homeostasis.
- Evaluation of pathological features of CKD.
Main Results:
- miR-4516 was downregulated and its target SIAH3 upregulated in CKD mouse kidneys.
- Melatonin injection increased miR-4516, decreased SIAH3, and enhanced PINK1/Parkin-mediated mitophagy.
- Melatonin treatment improved mitochondrial homeostasis and attenuated CKD pathological features.
Conclusions:
- The miR-4516/SIAH3 axis plays a critical role in regulating mitophagy in CKD.
- Melatonin activates the miR-4516/SIAH3/PINK1 mitophagy signaling pathway.
- Targeting this pathway with melatonin offers a potential therapeutic strategy for CKD.
