Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration

Jauhari, Abhishek; Баранов, С. В.; Suofu, Yalikun; Kim, Jin-Ho; Singh, Tanisha; Yablonska, Svitlana; Li, Fang; Wang, Xiaomin; Oberly, Patrick J.; Minnigh, M. Beth; Poloyac, Samuel M.; Carlisle, Diane L.; Friedlander, Robert M.

doi:10.1172/jci135026

Cited by 124 publications

(118 citation statements)

References 63 publications

(85 reference statements)

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“…However, it is generally unknown how melatonin promotes the osteogenic potential of bone marrow-derived MSCs undergoing aging. In this study, we found that melatonin in bone marrow was declined with aging, probably due to downregulation of the key rate-limiting enzymes AANAT and HIOMT in mitochondrion, which is consistent with a recent study indicating that AANAT could accelerate aging in a knockout mice model (32). Our study also suggests MMSET (also known as WHSC1 or NSD2) is an important factor mediating the effects of melatonin.…”

Section: Discussionsupporting

confidence: 92%

Melatonin Enhances Osteoblastogenesis from Senescent Mesenchymal Stem Cells via MMSET Mediated Chromatin Remodeling

Liu

Xie

Han

et al. 2021

Preprint

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Large numbers of elderly people have aging-associated osteoporosis, but efficient approaches to ameliorate bone loss are limited due to our poor understanding of the underlying mechanisms. In this study, we found that melatonin levels in bone marrow decreased with age, and melatonin primarily enhanced the osteogenic potential of mesenchymal stem cells (MSCs) derived from elderly donors compared with fetal- or young adult-derived MSCs. Mechanistic studies indicated melatonin treatment alleviated the senescence-related hypermethylation of the MMSET promoter, leading to elevated expression of the histone methyltransferase NSD2, and promoted the histone H3 dimethylation modification at lysine 36 of the osteogenic genes RUNX2 and SP7/OSTERIX as a consequence. MMSET depletion partially abolished the effects of melatonin on osteogenesis in senescent MSCs in vitro. Moreover, melatonin treatment promoted bone formation and alleviated the progression of osteoporosis in a mouse model of aging. Clinically, severity of senile osteoporosis (SOP) in patients was associated with melatonin levels in bone marrow plasma and the MMSET expression in MSCs, and melatonin treatment enhanced osteoblastogenesis from MSCs derived from SOP patients. Our study discovered a previously unreported epigenetic regulatory role for melatonin in alleviating MSC senescence and suggests that melatonin may be a potent agent for preventing aging-associated osteoporosis.

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Section: Discussionsupporting

confidence: 92%

Melatonin Enhances Osteoblastogenesis from Senescent Mesenchymal Stem Cells via MMSET Mediated Chromatin Remodeling

Liu

Xie

Han

et al. 2021

Preprint

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“…Pineal melatonin synthesis, however, usually diminishes with increasing age in both animals and humans [ 229 , 230 , 231 , 232 ]. This also presumably occurs at least to some degree in the mitochondria [ 233 ]. As a result, in elderly subjects, all cells exist in a relatively less-healthy state and the cells that become diseased (both neoplastic and non-neoplastic) persist as such both during the day and at night, allowing them to progress in their pathogenic condition at a greater frequency and a more rapid rate.…”

Section: Melatonin Reprograms Glucose Metabolism: Converting Diseamentioning

confidence: 99%

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

Reíter

Sharma

Rosales-Corral

2021

IJMS

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Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.

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“…The protective effects of melatonin are largely associated with its activity on mitochondria. For example, melatonin increases the activity of mitochondrial complexes 1, 3, and 4 [ 108 , 109 ], balances the mitochondrial membrane potential [ 110 ], reduces the duration of opening of the mitochondrial membrane permeability transition pore (mtPTP) [ 111 ], and maintains the ATP production [ 112 ]. Melatonin is classified as the mitochondrially targeted antioxidant [ 113 ].…”

Section: Mitochondria and Melatoninmentioning

confidence: 99%

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

Tan¹,

Hardeland

2020

Molecules

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Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen’s spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host’s tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.

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Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration

Cited by 124 publications

References 63 publications

Melatonin Enhances Osteoblastogenesis from Senescent Mesenchymal Stem Cells via MMSET Mediated Chromatin Remodeling

Melatonin Enhances Osteoblastogenesis from Senescent Mesenchymal Stem Cells via MMSET Mediated Chromatin Remodeling

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

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