ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy

Wang, Shuyi; Wang, Lin; Qin, Xing; Turdi, Subat; Sun, Dongdong; Culver, Bruce; Reíter, Russel J.; Wang, Xiaoming; Zhou, Hao; Ren, Jun

doi:10.1038/s41392-020-0171-5

Cited by 84 publications

(46 citation statements)

References 68 publications

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“…In this regard, MLT should be superior to other adjuvants in terms of safety, cost-effectiveness, and efficacy for large-scale cellular materials undergoing long-term expansion, although the comprehensive mechanisms are still under investigation. In regard to the therapeutic function of MLT, in vivo MLT application restored autophagic flux to impede cognitive decline and cardiac anomalies in Alzheimer’s disease (AD) animal models [ 27 , 28 ]. More recently, MLT was demonstrated to downregulate PI3K/AKT in stem cells through the MLT receptor (MT) [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

Tan

Dai

et al. 2021

Stem Cell Res Ther

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Background Stem cells that have undergone long-term ex vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potential. Due to its ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an adjuvant in long-term cell expansion protocols, but the mechanism underlying MLT-induced cell rejuvenation remains largely unknown. Methods Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex vivo for up to 15 passages, and cells from passages 2, 7, and 15 (P2, P7, and P15) were used to investigate cellular senescence and autophagy change in response to long-term expansion and indeed the following MLT treatment. Next, we examined whether MLT could induce cell rejuvenation by restoring the autophagic processes of damaged cells and explored the underlying signaling pathways. In this context, cellular senescence was indicated by senescence-associated β-galactosidase (SA-β-gal) activity and by the expression of senescence-related proteins, including p53, p21, p16, and γ-H2AX. In parallel, cell autophagic processes were evaluated by examining autophagic vesicles (by transmission electronic microscopy), autophagic flux (by assessing mRFP-GFP-LC3-transfected cells), and autophagy-associated proteins (by Western blot assay of Atg7, Beclin-1, LC3-II, and p62). Results We found that long-term in vitro passaging led to cell senescence along with impaired autophagy. As expected, MLT supplementation not only restored cells to a younger state but also restored autophagy in senescent cells. Additionally, we demonstrated that autophagy inhibitors could block MLT-induced cell rejuvenation. When the underlying signaling pathways involved were investigated, we found that the MLT receptor (MT) mediated MLT-related autophagy restoration by regulating the PI3K/AKT/mTOR signaling pathway. Conclusions The present study suggests that MLT may attenuate long-term expansion-caused cellular senescence by restoring autophagy, most likely via the PI3K/AKT/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the involvement of MT-dependent PI3K/AKT/mTOR signaling in MLT-induced autophagy alteration, indicating a potential of autophagy-restoring agents such as MLT to be used in the development of optimized clinical-scale cell production protocols.

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Section: Introductionmentioning

confidence: 99%

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

Tan

Dai

et al. 2021

Stem Cell Res Ther

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“…The property of MLT-mediated regulation of autophagy could also bene t in some age-related diseases. It was found that MLT in-vivo application ameliorated AD-induced cardiac atrophy [28], and enhanced the impeded cognitive function in tau-related AD rats [27] by restoring the autophagic ux. What's more, MLT could improve degradation of damaged mitochondria by mitophagy during aging and under neurodegenerative conditions [56].…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, it should be superior to other adjuvant in terms of safe, cost-effective and e cacy for large-scale of cellular materials undergone long-term expansion, despite the comprehensive mechanisms are still under investigation. When it comes to the therapeutic function of MLT, it is found that in-vivo MLT application could restore autophagic ux to impede cognitive decline and cardiac anomalies in Alzheimer disease (AD) animal models [27][28]. More recently, MLT demonstrated to down-regulate the PI3K/AKT in stem cells through MLT receptor (MT) [29].…”

mentioning

confidence: 99%

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Tan¹,

Xu²,

Dai³

et al. 2020

Preprint

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Background: Stem cells undergone long-term ex-vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potentials. Due to the ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an adjuvant across long-term cell expansion protocols, but the underlying mechanism remains largely unknown. Methods: Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex-vivo for 15 passages, and passage 2, 7 and 15 cells were used to interrogate the cellular senescence and alteration in cell autophagy during long-term expansion. The cellular senescence features were evidenced by senescence-associated β-galacotosidase (SA-β-gal) activity and the expression of senescence-related proteins including p53, p21, p16 and γ-H2AX. Electronic microscope was used to observe the autophagic vesicles. Adenovirus mRFP-GFP-LC3 was transfected to indicate the alteration of autophagic flux during long-term expansion, and the autophagy-associated proteins Atg7, Beclin-1, LC3-II and p62 were evaluated by Western blot. Results: It was found that long-term in-vitro passaging led to an accumulated SA-β-gal, elevated expressions of p53, p21, p16 and γ-H2AX, along with downregulated autophagy-associated proteins Atg7, Beclin-1 and LC3 as well as a mounting autophagy substrate p62. In accordance with expectation, supplemented with MLT not only ameliorated cells to a younger state but also restored the impaired autophagy level in senescent cells. Additionally, we demonstrated that autophagy inhibitor could block such MLT-induced cell rejuvenation. When the underlying signaling pathways involved was interrogated, we found that MLT receptor (MT) participated in mediating MLT-related autophagy restoration by regulating PI3K/AKT/mTOR signaling pathway.Conclusions: The present study suggests that MLT may rejuvenate long-term expansion-caused cellular senescence by restoring autophagy, more likely via PI3K/AKT/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the MT-dependent PI3K/AKT/mTOR signaling involved in MLT-induced autophagy alteration, pointing to a potential target for using autophagy-restoring agents such as MLT to develop optimized clinical-scale cell production protocols.

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“… 192 (Table 2 ) For example, in Alzheimer’s disease (AD)-associated cardiac dysfunction, mutations of AD genes PS1 (presenilin 1), and PS2 suppressed mitophagy and contractile function through downregulating the cGAS/STING signaling. 193 …”

Section: Roles Of Cgas In Human Autoimmune and Inflammation Diseasesmentioning

confidence: 99%

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Liu

2021

Sig Transduct Target Ther

121

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Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.

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ALDH2 contributes to melatonin-induced protection against APP/PS1 mutation-prompted cardiac anomalies through cGAS-STING-TBK1-mediated regulation of mitophagy

Cited by 84 publications

References 68 publications

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

Melatonin induces the rejuvenation of long-term ex vivo expanded periodontal ligament stem cells by modulating the autophagic process

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

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