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.
Highlights
Fibrosis is an excessive form of tissue injury repair, where wound healing becomes progressively uncontrolled and pathological [1]
We have previously demonstrated that melatonin can suppress ischemia-induced fibrosis in experimental models [16], and provide protective effects against renal cortical fibrosis by increasing the expression of miR-4516, a microRNA downregulated in the kidney cortex under chronic kidney disease (CKD) condition [17]
Our results suggest that mitophagy-defective chronic kidney injury can be attenuated or reversed by activating the miR-4516/SIAH3/PINK1 mitophagy signaling with melatonin
Summary
Fibrosis is an excessive form of tissue injury repair, where wound healing becomes progressively uncontrolled and pathological [1]. Pathological fibrosis leads to multiple organ dysfunction [2] and is the key contributor to poor outcome in many illnesses including chronic kidney disease (CKD) [3]. In CKD, fibrosis in kidney tissues negatively impacts renal function, and allows uremic toxins to remain in systemic circulation [4], leading to other conditions like myocardial fibrosis and resultant cardiovascular disease that propels the high mortality in late stage CKD patients [5]. Developing an effective treatment for reversing the pathological fibrosis in kidney has remained challenging [6]. Mechanisms such as mitochondrial fission, fusion, and autophagy, plays a critical role in the progression of renal fibrosis [7]. As observation of abnormal mitochondria accumulation in renal tubular cells is a characteristic of CKD [8], specific interventions to promote
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