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Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathwayopen access

Authors
Lee, Jun HeeYoon, Yeo MinSong, Keon-HyoungNoh, HyunjinLee, Sang Hun
Issue Date
Mar-2020
Publisher
Blackwell Publishing Inc.
Keywords
HSPA1L; melatonin; mesenchymal stem cells; mitochondria; mitophagy; replicative senescence
Citation
Aging Cell, v.19, no.3
Journal Title
Aging Cell
Volume
19
Number
3
URI
https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/3064
DOI
10.1111/acel.13111
ISSN
1474-9718
1474-9726
Abstract
Mesenchymal stem cells (MSCs) are a popular cell source for stem cell-based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin-induced HSPA1L binds to cellular prion protein (PrP (c)), resulting in the recruitment of PrP (c) into the mitochondria. The HSPA1L-PrP (c) complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti-oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin-treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control.
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College of Medicine > Department of Biochemistry > 1. Journal Articles
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