Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

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 (PrPC), resulting in the recruitment of PrPC into the mitochondria. The HSPA1L‐PrPC 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.

Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

“…Cultured MSCs undergo progressive replicative senescence accompanied by mitochondrial dynamic changes, excessive ROS generation, and decreased mitochondrial membrane potential [ 23 ]. Melatonin pretreatment rescues MSC from replicative senescence by restoring mitochondrial dynamics, reducing ROS generation and maintaining membrane potential through upregulating heat shock protein 1L (HSPA1L) [ 18 ].…”

“…Melatonin pretreatment rescues MSC from replicative senescence by restoring mitochondrial dynamics, reducing ROS generation and maintaining membrane potential through upregulating heat shock protein 1L (HSPA1L) [ 18 ]. HSPA1L, a member of HSP70 family [ 77 ], functions as a chaperone protein facilitating protein folding and stabilizing prion protein Prp c [ 23 ]. Prp c regulates mitochondrial integrity and function through binding to HSPA1L.…”

“…Recent studies indicate that tryptophan metabolites produced via the tryptophan hydroxylase (TPH) pathway defend against replicative and hyperglycemia or oxidative stress-induced cell senescence. 5-methoxytryptophan (5-MTP) was reported to rescue bone marrow mesenchymal stromal cells (BM-MSCs) from high glucose (HG)-induced senescence [ 22 ], while melatonin protects MSC from replicative and stress-induced senescence [ 23 ]. Melatonin and 5-MTP represent a new class of senomorphic compounds which may be useful in protecting MSC against senescence and age-related diseases.…”

Melatonin in Wine and Beer: Beneficial Effects

“…Recent evidence suggest that MEL secretion can be dysregulated in MS patients, proposing that MEL could be a potential target for therapeu-tic intervention in the patients. Moreover, MEL protects against neurodegeneration and senescence associated with oxidative stress through the reduction in p-p38, inhibition of p16INK4α and increase in SIRT1 [ 92 ].…”

Potential Preventive Strategies for Amyotrophic Lateral Sclerosis

“…D (Camu et al, 2014;Paganoni et al, 2017;Wang et al, 2017) IE (Karam et al, 2013) (Piquet, 2006;Ngo et al, 2017;Harrison et al, 2018), IE (ALSUntangled, 2014; Gianforcaro and Hamadeh, 2014;Lu'o'ng and Nguyễn, 2013), P (Sherry, 2017;ALSUntangled Group, 2018) Vit. E (Wang et al, 2011), IE (Mattson et al, 2002;Veldink et al, 2007;Patel and Hamadeh, 2009;Luo and Dun, 2013) ( Desnuelle et al, 2001;Nieves et al, 2016;Ngo et al, 2017), IE (Mattson et al, 2002), P (Sherry, 2017) Magnesium (Longnecker et al, 2000) (Ngo et al, 2017), P (Machlan, 2012;Sherry, 2017;ALSUntangled Group, 2018) Selenium (Harrison et al, 2018), P (Shackel, 2014) Polyunsaturated fatty acids (Veldink et al, 2007), IE (Fitzgerald et al, 2014) (Harrison et al, 2018), P (Shackel, 2014;Sherry, 2017) Melatonin (Sofic et al, 2005), IE (Patel and Hamadeh, 2009;Lee et al, 2020) IE (Iacovitti et al, 1997;Jacob et al, 2002), P (Sherry, 2017) Q10 IE (Patel andHamadeh, 2009) (Jacob et al, 2002;…”