Dysfunctional mitochondria in age-related neurodegeneration: Utility of melatonin as an antioxidant treatment

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 101, P. 102480 - 102480

Published: Sept. 3, 2024

Mitochondria functionally degrade as neurons age. Degenerative changes cause inefficient oxidative phosphorylation (OXPHOS) and elevated electron leakage from the transport chain (ETC) promoting increased intramitochondrial generation of damaging reactive oxygen nitrogen species (ROS RNS). The associated progressive accumulation molecular damage causes an increasingly rapid decline in mitochondrial physiology contributing to aging. Melatonin, a multifunctional free radical scavenger indirect antioxidant, is synthesized matrix neurons. Melatonin reduces ETC elevates ATP production; it also detoxifies ROS/RNS via SIRT3/FOXO pathway upregulates activities superoxide dismutase 2 glutathione peroxidase. influences glucose processing by In neurogenerative diseases, often adopt Warburg-type metabolism which excludes pyruvate mitochondria causing reduced acetyl coenzyme A production. Acetyl supports citric acid cycle OXPHOS. Additionally, required co-substrate for arylalkylamine-N-acetyl transferase, rate limits melatonin synthesis; therefore, production diminished cells that experience making more vulnerable stress. Moreover, endogenously produced diminishes during aging, further increasing components. More normal preserved aging with supplementation.

Language: Английский

---

Melatonin-mediated actions and circadian functions that improve implantation, fetal health and pregnancy outcome

Reproductive Toxicology, Journal Year: 2024, Volume and Issue: 124, P. 108534 - 108534

Published: Jan. 6, 2024

Language: Английский

---

The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Clinical and Translational Neuroscience, Journal Year: 2024, Volume and Issue: 8(1), P. 11 - 11

Published: Feb. 2, 2024

Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of glymphatic system, which mainly active during sleep. Changes in sleep circadian are present not only overt neurodegenerative diseases but also their early, prodromal, preclinical phases, supporting they precede (and contribute to) development This narrative review provides brief overview rhythm disruption neurodegeneration, highlights changes addresses future perspectives, particular, whether able to predict neurodegeneration potential actionability prevent or modulate diseases.

Language: Английский

---

Circadian regulation in aging: Implications for spaceflight and life on earth

Aging Cell, Journal Year: 2023, Volume and Issue: 22(9)

Published: July 26, 2023

Abstract Alterations in the circadian system are characteristic of aging on Earth. With decline physiological processes due to aging, several health concerns including vision loss, cardiovascular disorders, cognitive impairments, and muscle mass loss arise elderly populations. Similar risks reported as “red flag” among astronauts during after a long‐term Space exploration journey. However, little is known about common molecular alterations underlying terrestrial space‐related astronauts, controversial conclusions have been recently reported. In light regulatory role clock maintenance human health, we review here overlapping both Earth spaceflight with focus four most affected systems: visual, cardiovascular, central nervous, musculoskeletal systems. this review, briefly introduce specific cellular followed by those aging. We next summarize associated spaceflight, highlighting involved clock‐regulated genes space flown Drosophila , nematodes, small mammals, astronauts. Finally, discuss that altered terms their expression spaceflight. Altogether, data elaborated strengthen our hypothesis regarding timely need include dysregulation an emerging hallmark beyond.

Language: Английский

---

Traumatic Brain Injury, Sleep, and Melatonin—Intrinsic Changes with Therapeutic Potential

Clocks & Sleep, Journal Year: 2023, Volume and Issue: 5(2), P. 177 - 203

Published: April 6, 2023

Traumatic brain injury (TBI) is one of the most prevalent causes morbidity in United States and associated with numerous chronic sequelae long after point injury. One common long-term complaints patients TBI sleep dysfunction. It reported that alterations melatonin follow may be linked various circadian disorders directly (via cellular signaling) or indirectly free radicals inflammatory signaling). Work over past two decades has contributed to our understanding role as a regulator neuroprotective anti-inflammatory agent. Although there increasing interest treatment insomnia following TBI, lack standardization rigor research left behind trail non-generalizable data ambiguous recommendations. This narrative review describes underlying biochemical properties they are relevant TBI. We also discuss potential benefits path forward regarding therapeutic management treatment, including its neuroprotectant, somnogen, modulator rhythm.

Language: Английский

---

New Perspectives on the Role and Therapeutic Potential of Melatonin in Cardiovascular Diseases

American Journal of Cardiovascular Drugs, Journal Year: 2024, Volume and Issue: 24(2), P. 171 - 195

Published: March 1, 2024

Language: Английский

---

Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer’s disease

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 4, 2025

Background: Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) AD through bioinformatic analysis. Methods: First, key cells single-cell dataset GSE138852 were screened out based proportion annotated and Fisher's test between control groups. The differentially expressed (DEGs) cell GSE5281 datasets identified, MRGs selected via weighted gene coexpression network After intersecting two sets DEGs MRGs, we performed Mendelian randomization analysis to identify causally related AD. Biomarkers further ascertained receiver operating characteristic curve (ROC) expression GSE48350. Furthermore, set enrichment analysis, immune infiltration correlation with metabolic pathways conducted, as well construction a regulator molecular docking. Results: According Fisher test, oligodendrocytes regarded due their excellent abundance dataset, which there 281 overlapping 3,490 550 GSE5281, four found be AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) RAS association domain 4(RASSF4). Moreover, GPRC5B, NFKBIA RASSF4 deemed biomarkers, except for METTL7A, because indistinctive might involved oxidative phosphorylation, adipogenesis heme metabolism. T helper type 17 cells, natural killer CD56dim significantly correlated biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) regulate Finally, discovered that all biomarkers could bind MLT strong binding energy. Conclusion: Our study identified three novel RASSF4, providing approach investigation treatment

Language: Английский

---

Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

---

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2023, Volume and Issue: unknown, P. 962 - 993

Published: Oct. 25, 2023

A dysregulated circadian rhythm is significantly associated with cancer risk, as aging. Both aging and dysregulation show suppressed pineal melatonin, which indicated in many studies to be linked risk progression. Another independently investigated aspect of the cortisol awakening response (CAR), stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR HPA activity are primarily mediated via activation glucocorticoid receptor (GR), drives patterned gene expression binding promotors element (GRE)-expressing genes. Recent data shows that GR can prevented from nuclear translocation by B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), translocates mitochondria, where it have diverse effects. Melatonin also suppresses maintaining a complex heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, upregulate BAG-1, suggesting dramatic 10-fold decrease melatonin adolescence ninth decade life will attenuate capacity night-time modulate effects early morning CAR. The interactions melatonin/BAG-1/Hsp90 proposed underpin how risk. This may differential melatonin/BAG-1/Hsp90/GR different cells microenvironments across body, tumors emerge. provides model pathogenesis better integrates previously disparate bodies data, including immune regulated tumor microenvironment, at least partly regulation tryptophan-melatonin pathway. has number future research treatment implications.

Language: Английский

---

Polycystic Ovary Syndrome Pathophysiology: Integrating Systemic, CNS and Circadian Processes

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(1), P. 24 - 24

Published: Jan. 18, 2024

The conceptualization of polycystic ovary syndrome (PCOS) has primarily focused on hormonal alterations driven by changes within the hypothalamus and ovarian granulosa cells, with treatment contraceptive pill weight loss. However, a growing body data implicates wider systemic central nervous system (CNS) in pathoetiology pathophysiology PCOS, consequent implications for targeted treatments. It is proposed that there significant role night-time interactions factors acting to regulate whether rising level cortisol over night during morning awakening response (CAR) able induce nuclear translocation glucocorticoid receptor (GR), thereby influencing how immune glial systems cellular function preparation coming day. Factors affording protection PCOS also inhibit GR including gut microbiome-derived butyrate, pineal/local melatonin as well regulated bcl2-associated athanogene (BAG)-1. A pathophysiological attributed aryl hydrocarbon (AhR), which shows heightened levels activity PCOS. AhR activated ligands many processes, white adipocyte-derived kynurenine, implicating obesity occurring ovaries. activation consequences physiological hypothalamic paraventricular nucleus, cells adipocytes, partly mediated upregulation mitochondrial N-acetylserotonin/melatonin ratio, decreasing availability whilst increasing local stress plasticity nucleus. This article reviews detail CNS highlighting pineal melatonergic pathway, nucleus tanycytes/astrocytes, hypothalamus-pituitary-adrenal (HPA) axis pathophysiology. integrates wide array previously disparate biological underpinnings associates other currently classified medical conditions, such depression, bipolar disorder, type 1 diabetes mellitus autism spectrum. Numerous future research are detailed.

Language: Английский

---