Journal of Pineal Research最新文献

{"title":"Circadian Rhythm Disruption in Triple-Negative Breast Cancer: Molecular Insights and Treatment Strategies","authors":"Li-Hua He,&nbsp;Xin-Yi Sui,&nbsp;Yu-Ling Xiao,&nbsp;Peng Ji,&nbsp;Yue Gong","doi":"10.1111/jpi.70042","DOIUrl":"https://doi.org/10.1111/jpi.70042","url":null,"abstract":"<div>\u0000 \u0000 <p>Disruption of the circadian clock has been closely linked to the initiation, development, and progression of cancer. This study aims to explore the impact of circadian rhythm disruption (CRD) on triple-negative breast cancer (TNBC). We analyzed bulk and single-cell RNA sequencing data to assess circadian rhythm status in TNBC using multiple bioinformatic tools, alongside metabolomic profiles and tumor microenvironment evaluations to understand the influence of CRD on metabolic reprogramming and immune evasion. The results indicate that TNBC experiences profound CRD. Patients with a higher CRDscore exhibit significantly poorer relapse-free survival compared to those with a lower CRDscore. Cyclic ordering by periodic structure (CYCLOPS) identified significant changes in rhythmic gene expression patterns between TNBC and normal tissues, with TNBC showing a “rush hour” effect, where peak expression times are concentrated within specific time windows. Transcripts with disrupted circadian rhythms in TNBC were found to be involved in key pathways related to cell cycle regulation, metabolism, and immune response. Metabolomic analysis further revealed that TNBCs with high CRDscore are enriched in carbohydrate and amino acid metabolism pathways, notably showing upregulation of tryptophan metabolism. High CRDscore was also linked to an immunosuppressive tumor microenvironment, characterized by reduced immune cell infiltration, exhausted CD8⁺ T cells, and a diminished response to immune checkpoint blockade therapy. These findings suggest that the disrupted molecular clock in TNBC may activate tryptophan metabolism, thereby promoting immune evasion and potentially reducing the effectiveness of immunotherapy.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Repairs the Lipidome of Human Hepatocytes Exposed to Cd and Free Fatty Acid-Induced Lipotoxicity","authors":"Anna Migni,&nbsp;Desirée Bartolini,&nbsp;Giada Marcantonini,&nbsp;Roccaldo Sardella,&nbsp;Mario Rende,&nbsp;Alessia Tognoloni,&nbsp;Maria Rachele Ceccarini,&nbsp;Francesco Galli","doi":"10.1111/jpi.70047","DOIUrl":"https://doi.org/10.1111/jpi.70047","url":null,"abstract":"<p>Hepatocyte lipotoxicity is central to the aetiology of nonalcoholic fatty liver disease (NAFLD), a leading cause of liver failure and transplantation worldwide. Long-lasting toxic pollutants have increasingly been considered as environmental risk factors of NAFLD. These include cadmium (Cd), a metal that synergizes with other cellular toxicants and metabolic stimuli to induce fat build-up and lipotoxicity. Recent studies demonstrated that melatonin (MLT) holds great potential as repairing agent in this form of hepatocyte lipotoxicity. In this study, the molecular hints of this MLT effect were investigated by lipidomics analysis in undifferentiated HepaRG cells, a human pre-hepatocyte cell line, exposed to Cd toxicity either alone or combined with prototypical free fatty acids (FFA), namely the saturated species palmitic acid and the monounsaturated oleic acid (OA and PA, respectively), to simulate the cellular lipotoxicity conditions of fatty liver disease. Cd exposure synergized with FFAs to induce cellular steatosis, and PA produced higher levels of lipotoxicity compared to OA by leading to increased levels of H₂O₂ production and apoptotic death. These effects were associated with changes of the cellular lipidome, which approximate those of NAFLD liver, with differentially expressed lipids in different classes that included triacylglycerols (TG), di- and mono-acylglycerols, phospholipids (PL), sphingolipids, acylcarnitines and FA; characteristic differences were observed in all these classes comparing the combinations of Cd exposure with PA or OA treatments. MLT significantly reduced the effects of either individual or combinatorial treatments of Cd and FFAs on lipotoxicity hallmarks, also repairing most of the alterations of the cellular lipidome, including those of the chain length and number of double bonds of acyl residues esterified to TG and PL classes. These findings and their bioinformatics interpretation suggest a role for the earliest acyl elongase and desaturase steps of FA metabolism in this repairing effect of MLT; biochemistry studies validated such interpretation identifying a specific role for SCD1 activity. This lipidomics study shed light on the cytoprotective mechanism of MLT in Cd and FFA-induced hepatocyte lipotoxicity, highlighting a repairing effect of this molecule on the cellular lipidome, which may hold therapeutic potential in fatty liver diseases.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a COMT Gene Involved in the Biosynthesis of Melatonin Which Mediates Resistance to Citrus Canker","authors":"Kun Yang,&nbsp;Wenqing Xu,&nbsp;Huanyu Cai,&nbsp;Xiaomei Tang,&nbsp;Xiaoyan An,&nbsp;Chunyang He,&nbsp;Huailong Teng,&nbsp;Qiang Xu,&nbsp;Yuantao Xu","doi":"10.1111/jpi.70043","DOIUrl":"https://doi.org/10.1111/jpi.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Citrus canker, caused by <i>Xanthomonas citri</i> subsp <i>citri</i> (<i>Xcc</i>), represents a severe threat to the citrus industry. The conventional control measures for citrus canker primarily rely on chemical bactericide. However, overuse of bactericide will cause environmental and food security concerns. To address this problem, efforts are being made to develop environmentally friendly bio-bactericide alternatives. In this study, we identified a caffeic acid O-methyltransferase gene, <i>AbCOMT1</i>, from <i>Atalantia buxifolia</i>, a <i>Citrus</i>-related species exhibiting high resistance to citrus canker. <i>AbCOMT1</i> encodes a key enzyme involved in melatonin biosynthesis, and its overexpression in sweet orange significantly enhances resistance to citrus canker. We found elevated melatonin levels in the <i>AbCOMT1</i> overexpressing sweet orange lines and demonstrated that the <i>AbCOMT1</i> overexpression not only directly inhibited <i>Xcc</i> proliferation but also activated citrus immune responses. To further improve the inhibitory efficacy of melatonin, we tested several melatonin derivatives, achieving a tenfold increase in inhibitory activity. Notably, the melatonin derivative MT-3 exhibited outstanding efficacy in controlling citrus canker under field conditions. Our results revealed <i>AbCOMT1</i> as a promising resistance gene and identified the highly efficient melatonin derivatives for citrus canker disease control.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Pinealectomy Syndrome and the Impact of Melatonin Replacement Therapy: 1-Cardiovascular Function","authors":"Claudia Cosentino,&nbsp;Fernanda Gaspar do Amaral,&nbsp;Luciana Aparecida Campos,&nbsp;Fernanda Gentil,&nbsp;Osmar Pinto Neto,&nbsp;Andréa Maria Cappellano,&nbsp;Nasjla Saba da Silva,&nbsp;Ovidiu Constantin Baltatu,&nbsp;José Cipolla-Neto","doi":"10.1111/jpi.70045","DOIUrl":"https://doi.org/10.1111/jpi.70045","url":null,"abstract":"<div>\u0000 \u0000 <p>The purpose of this investigational study was to assess the cardiovascular effects of melatonin replacement therapy in pinealectomized patients. This was a prospective open-label, single-arm proof-of-concept study The study comprised 11 patients aged 16.7 ± 1.7 years, who had undergone pinealectomy, experienced no tumor recurrence, and exhibited undetectable salivary melatonin levels. A 6-month melatonin regimen (0.3 mg daily) was administered. Ambulatory blood pressure monitoring was conducted at baseline, 3-month, and 6-month intervals. First of all, no hypertension was observed in pinealectomized patients. Over the course of the study, diastolic blood pressure progressively decreased, reaching statistical significance at 6 months. Pulse pressure exhibited a gradual increase, reaching statistical significance after 6 months. Short-term blood pressure variability increased significantly for both systolic and diastolic pressures. Morning systolic and diastolic blood pressure levels were significantly decreased by melatonin replacement therapy. Melatonin had no effect on the average heart rate or its variability. Melatonin-deficient pinealectomized patients were normotensive. Melatonin replacement in these patients led to reduced diastolic pressure, increased pulse pressure, and enhanced short-term blood pressure variability. These results are consistent with improved cardiovascular health. Furthermore, melatonin's temporal specificity suggests that it might enhance nighttime recovery, heightening reactivity during wakefulness. While melatonin is used as a dietary supplement for similar effects, caution is advised, and further research is needed to optimize its use in various health and disease contexts. Further, considering the study's limitations, more extensive research would strengthen these findings.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Pineal to Biological Rhythms Through Melatonin","authors":"Horst-Werner Korf,&nbsp;Gianluca Tosini","doi":"10.1111/jpi.70044","DOIUrl":"https://doi.org/10.1111/jpi.70044","url":null,"abstract":"","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orphan GPR50 Restrains Neurite Outgrowth and Cell Migration by Activating the G12/13 Protein-RhoA Pathway in Neural Progenitor Cells and Tanycytes","authors":"Raise Ahmad,&nbsp;Marine Luka,&nbsp;Anne-Sophie Journe,&nbsp;Sarah Gallet,&nbsp;Alan Hegron,&nbsp;Marcio Do Cruzeiro,&nbsp;Mark J. Millan,&nbsp;Philippe Delagrange,&nbsp;Bernard Masri,&nbsp;Julie Dam,&nbsp;Vincent Prevot,&nbsp;Ralf Jockers","doi":"10.1111/jpi.70041","DOIUrl":"https://doi.org/10.1111/jpi.70041","url":null,"abstract":"<p>Human genetic variants of the orphan G protein-coupled receptor GPR50 are suggested risk factors for neuropsychiatric disorders. However, the function of GPR50 in the central nervous system (CNS) and its link to CNS disorders remain poorly defined. Here, we generated GPR50 knockout (GPR50-KO) mice and show that the absence of GPR50 increases neurite outgrowth, cell motility and migration of isolated neural progenitor cells (NPCs) and hypothalamic radial glial cells (tanycytes). These observations were phenocopied in NPCs and tanycytes from wild-type mice treated with neutralizing antibodies the against the prototypical neurite growth inhibitor Nogo-A. Treatment of NPCs and tanycytes from GPR50-KO cells with neutralizing antibodies had no further, additive, effect. Inhibition of neurite growth by GPR50 occurs through activation of the G_12/13 protein-RhoA pathway in a manner similar to, but independent of Nogo-A and its receptors. Collectively, we show that GPR50 acts as an inhibitor of neurite growth and cell migration in the brain by activating the G_12/13 protein-RhoA pathway.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Specific Methylomic and Transcriptomic Responses of the Avian Pineal Gland to Unpredictable Illumination Patterns","authors":"Fábio Pértille,&nbsp;Tejaswi Badam,&nbsp;Nina Mitheiss,&nbsp;Pia Løtvedt,&nbsp;Emmanouil Tsakoumis,&nbsp;Mika Gustafsson,&nbsp;Luiz Lehmann Coutinho,&nbsp;Per Jensen,&nbsp;Carlos Guerrero-Bosagna","doi":"10.1111/jpi.70040","DOIUrl":"https://doi.org/10.1111/jpi.70040","url":null,"abstract":"<p>In the production environment of chickens, exposure to unpredictable light patterns is a common painless stressor, widely used to influence growth rate and egg production efficiency. The pineal gland, a key regulator of circadian rhythms through melatonin secretion, responds to environmental light cues, and its function is modulated by epigenetic mechanisms. In this study, we investigated how the pineal gland methylome and transcriptome (including micro-RNAs) interact to respond to a rearing exposure to unpredictable illumination patterns, with a particular focus on sex differences. We conducted an integrative multi-omic analysis—including methylomic (MeDIP-seq), transcriptomic (RNA-seq), and miRNA expression profiling—on the pineal gland of Hy-Line White chickens (<i>n</i> = 34, 18 females, 16 males) exposed to either a standard 12:12 light–dark cycle (control) or a randomized, unpredictable light schedule from Days 3 to 24 post-hatch. Our findings reveal that unpredictable light exposure alters the pineal gland methylome and transcriptome in a sex-specific manner. However, while transcriptomic differences between sexes increased due to the stress, methylomic differences decreased, particularly on the Z chromosome. These changes were driven by females (the heterogametic sex in birds), which became more male-like in their pineal methylome after exposure to the illumination stress, leading to reduced epigenetic sexual dimorphism while maintaining differences at the gene expression level. Further, we implemented a fixed sex effect model as a biological proof of concept, identifying a network of 12 key core genes interacting with 102 other genes, all linked to circadian regulation and stress adaptation. This network of genes comprises a core regulatory framework for circadian response. Additionally, tissue-specific expression analysis and cell-type specific expression analysis revealed enrichment in brain regions critical for circadian function, including neuronal populations involved in circadian regulation and the hypothalamic–pituitary–thyroid axis. Together, these findings provide strong evidence of sex-specific epigenetic transcriptomic responses of the pineal gland upon illumination stress and offer valuable insights into the interplay of different omic levels in relation to circadian response.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Increased Autophagy Level to Facilitate Osteogenesis of Inflamed PDLSCs Through TMEM110 Signaling Pathways","authors":"Xinyue Xu,&nbsp;Zhaojia Zhang,&nbsp;Wen Tian,&nbsp;Meng Cao,&nbsp;Zhen Wang,&nbsp;Fei Li,&nbsp;Tian Gao,&nbsp;Mengjuan Cheng,&nbsp;Yunlong Xia,&nbsp;Jinlong Shao,&nbsp;Chunxu Hai","doi":"10.1111/jpi.70039","DOIUrl":"https://doi.org/10.1111/jpi.70039","url":null,"abstract":"<p>Periodontal ligament stem cells (PDLSCs) bring new hope to patients with poor periodontium recovery and impaired regeneration. However, the complex inflammatory microenvironment continually inhibits stem cell function and hinders stem cell therapy effectiveness. Melatonin is a naturally occurring neurohormone that participates in the regulation of a large spectrum of biological functions. We investigated the effect of melatonin on periodontium regeneration both in vitro and in vivo. The results showed that melatonin promoted periodontitis recovery and enhanced the osteogenesis of inflamed PDLSCs (Inf-PDLSCs) depending on concentrations. Further mechanistic exploration indicated that autophagy activation played a significant role in enhancing the osteogenic differentiation of Inf-PDLSCs after melatonin treatment. Additionally, melatonin-induced upregulation of TEME110 participated in the initiation of autophagy activation and enhancement of osteogenesis in Inf-PDLSCs. Collectively, the results of our study provide evidence that melatonin-mediated osteogenesis of Inf-PDLSCs is important for periodontal tissue regeneration. Moreover, melatonin as a therapeutic drug for periodontitis treatment deserves further investigation.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Antifungal Activity of Melatonin Derivatives Containing a (Thio)Semicarbazide Group","authors":"Jing-Rui Liu,&nbsp;En-Yu Jiang,&nbsp;Chun-Bao Duan,&nbsp;Lan Cheng,&nbsp;Zhaoxia Chen,&nbsp;Yulong Li,&nbsp;Fan Wang,&nbsp;Qiang Bian,&nbsp;Otgonpurev Sukhbaatar,&nbsp;Qi Sun,&nbsp;Ming-Zhi Zhang,&nbsp;Wei-Hua Zhang,&nbsp;Yu-Cheng Gu","doi":"10.1111/jpi.70038","DOIUrl":"https://doi.org/10.1111/jpi.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Melatonin is a natural hormone that has functions such as circadian rhythm regulation, neuroregulation and cardiac protection, as well as antifungal activity. In this study, two series of melatonin derivatives containing a semicarbazide or a thiosemicarbazide group were designed and synthesized. The antifungal screening results indicated that compound <b>III-9</b> exhibited a broad antifungal spectrum against six phytopathogenic fungi at 50 µg/mL, with over 60% growth inhibition, and this is highlighted by its inhibition rates of 80.8% and 87.2% against <i>Botrytis cinerea</i> and <i>Rhioctorzia solani</i>, respectively, which was superior to the commercial fungicide Osthole. It also showed moderate antifungal activity in vivo against Cucumber <i>botrytis cinerea</i>, <i>Sclerotinia sclerotiorum</i>, and <i>Phytophthora capsica</i> at 200 µg/mL. And the scanning electron microscope (SEM), molecular docking, and enzymatic activity results provided insights into the potential mechanisms underlying the antifungal activity of these derivatives, which might target succinate dehydrogenase (SDH). Study of structure–activity relationships (SAR) and pesticide-likeness prediction offered valuable guidance for the future structural optimization of melatonin derivatives.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Deficits Result in Pathologic Metabolic Reprogramming in Differentiated Neurons","authors":"Abhishek Jauhari,&nbsp;Adam C. Monek,&nbsp;Yalikun Suofu,&nbsp;Olivia R. Amygdalos,&nbsp;Tanisha Singh,&nbsp;Sergei V. Baranov,&nbsp;Diane L. Carlisle,&nbsp;Robert M. Friedlander","doi":"10.1111/jpi.70037","DOIUrl":"https://doi.org/10.1111/jpi.70037","url":null,"abstract":"<p>Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial-triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine <i>N</i>-acetyltransferase knockout (AANAT-KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT-KO deficiency elevated BAK and BAX levels in AANAT-KO neurons. Further, we found that exogenous melatonin treatment of AANAT-KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 2","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}