bims-mistre 2025-10-19 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–10–19
23 papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.
HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.
Mitochondrial dysfunction as a therapeutic nexus in HFpEF: therapeutic target and pharmacological advances.
Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction.
Polycystic Ovary Syndrome May Be Associated With a Novel Mitochondrial tRNAAsp Mutation.
Disruption of Gut Microbiota-Mediated De Novo NAD+ Synthesis Contributes to the Development of Polycystic Ovary Syndrome.
The mitochondrial side of frailty.
Effects of Nicotinamide Mononucleotide Supplementation and Aerobic Exercise on Metabolic Health and Physical Performance in Aged Mice.
Vitamin C conveys geroprotection on primate ovaries.
cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives.
Oxidative Stress, Mitochondrial Quality Control, Autophagy, and Sirtuins in Heart Failure.
Burning the candle at both ends: ROS-mediated telomere damage drives T cell dysfunction.
Functions of Estrogen and Estrogen-Related Receptors in Diseases of the Female Reproductive System.
Daily life stress is linked to increased glucose levels in individuals with insulin resistance: a real-world assessment.
Potential Therapeutic Effects of Oolong Tea Phytochemicals on NLRP3 Inflammasome Assembly and Oxidative Stress.
Morin enhances healthspan and neuroprotection in Caenorhabditis elegans via mitochondrial stress adaptation.
IDO Inhibition by 1-Methyltryptophan: Unlocking New Paths to Treat Ovarian Dysfunction and Hormonal Imbalance in PCOS.
The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms.
NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
Men's brains shrink faster than women's: what that means for Alzheimer's.
Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway.
Anti-fatigue and antioxidative effects of amino acid (Leu, Gln, Cys)-EGCG complex via NRF2 and PGC-1α pathways: insights from cellular, animal, and pilot clinical studies.
Sex Dimorphism and Substrate Dependency of Liver Mitochondrial Bioenergetics and H2O2 Production.

Nat Metab. 2025 Oct 14.

Mitochondrial and psychosocial stress-related regulation of FGF21 in humans.

Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.

Fibroblast growth factor 21 (FGF21) is a metabolic hormone induced by fasting, metabolic stress and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (P < 0.0001) in healthy controls, but increases FGF21 by 32% (P < 0.0001) in people with MitoD, pointing to a functional FGF21 interaction between the stress response and OxPhos capacity. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report associations between FGF21 and psychosocial factors related to stress and wellbeing. Overall, these results highlight a potential role for FGF21 as a stress hormone involved in meeting the energetic needs of psychosocial stress.

DOI: https://doi.org/10.1038/s42255-025-01388-6
Open Biol. 2025 Oct;15(10): 240376

HMGB1 and mitochondrial dysfunction: a double-edged sword in ageing.

Maheen Wahid, Margaret Cunningham.

  Ageing is an intricate and progressive decline across all biological systems, marked by various molecular and cellular processes termed as the hallmarks of ageing. One of the hallmarks is mitochondrial dysfunction, which is brought about through several pathways: mutations in mitochondrial DNA, elevated reactive oxygen species production, disrupted mitochondrial dynamics and impaired mitophagy. Here, we explore the role of high mobility group box 1 (HMGB1) as a potential contributor to mitochondrial dysfunction, examining how it may influence these pathways through its dual roles as both a protector of mitochondrial integrity and a promoter of inflammatory damage. Furthermore, we consider how mitochondrial dysfunction, possibly mediated by HMGB1, could link to other hallmarks of ageing, positioning HMGB1 as a possible central regulator in the ageing process.

Keywords:  HMGB1; ageing; mitochondrial dysfunction

DOI:  https://doi.org/10.1098/rsob.240376
Front Pharmacol. 2025 ;16 1676988

Mitochondrial dysfunction as a therapeutic nexus in HFpEF: therapeutic target and pharmacological advances.

Tian Yue, Dezhi Zheng, Jian He, Shiqiang Xiong, Junbo Xu, Jun Hou.

  Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately 50% of all HF cases, and its incidence continues to rise with population aging and the surge in metabolic diseases. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF lacks effective therapeutic regimens to improve prognosis, with a 5-year mortality rate as high as 50%. Mitochondrial dysfunction, as a key link connecting metabolic disorders and abnormal myocardial systolic and diastolic function, has become a critical mechanism in the pathophysiology of HFpEF and a potential therapeutic target. This review systematically elaborates on the molecular mechanisms in HFpEF, such as mitochondrial energy metabolism disorders, dynamic imbalance, oxidative stress injury, and calcium signal dysregulation, comprehensively reviews the evidence for the effects of marketed drugs and drugs in clinical trials that improve mitochondrial function, and simultaneously explores emerging therapeutic strategies targeting mitochondria. This review aims to provide a theoretical reference for mechanistic research and drug development of HFpEF and promote the application of precision therapy targeting mitochondrial dysfunction in clinical practice.

Keywords:  HFpEF; drug development; mitochondrial dysfunction; mitochondrial targeting; therapeutic strategies

DOI:  https://doi.org/10.3389/fphar.2025.1676988
Int J Mol Sci. 2025 Oct 06. pii: 9715. [Epub ahead of print]26(19):

Obesity-Driven Metabolic Disorders: The Interplay of Inflammation and Mitochondrial Dysfunction.

Wooyoung Choi, Gun Ha Woo, Tae-Hwan Kwon, Jae-Han Jeon.

  Obesity contributes to the development of metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained low-grade inflammation and mitochondrial dysfunction. In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates β-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function-including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy-may retard disease progression.

Keywords:  inflammation; metabolic disorder; mitochondrial dysfunction; obesity

DOI:  https://doi.org/10.3390/ijms26199715
Hum Mutat. 2025 ;2025 6663471

Polycystic Ovary Syndrome May Be Associated With a Novel Mitochondrial tRNAAsp Mutation.

Yu Ding, Xuejiao Yu, Jian Xu, Caijuan Zhang, Jianhang Leng.

  Polycystic ovary syndrome is a common clinical condition often linked to insulin resistance (IR) and primarily affects women at reproductive age. Previous research has indicated a close association between mitochondrial tRNA (mt-tRNA) mutations and this syndrome; however, the range of mt-tRNA mutations in PCOS-IR remains largely unclear. In this study, we examined mt-tRNA mutations in 302 Han Chinese women with PCOS-IR and 589 control subjects, identifying a novel m.7544C>T mutation potentially related to this syndrome. At the molecular level, the m.7544C>T mutation occurs at a highly conserved nucleotide within the anticodon stem of mt-tRNAAsp, disrupting the 30C-40G base-pairing. Using cybrids cells derived from two individuals carrying this mutation and two controls without it, we observed that the m.7544C>T decreased the steady-state levels of tRNAAsp, altered mitochondrial RNA transcripts, impaired the activities of respiratory chain enzymes and oxygen consumption rates (OCRs), compromised mitochondrial functions, and increased oxidative stress. Overall, our findings strongly suggest that the m.7544C>T mutation contributes to the development of PCOS-IR, offering new insights into the pathophysiology of PCOS-IR driven by tRNA mutation-induced mitochondrial dysfunction and oxidative stress.

Keywords:  PCOS-IR; mitochondrial dysfunction; mt-tRNAAsp; novel m.7544C>T mutation

DOI:  https://doi.org/10.1155/humu/6663471
Adv Sci (Weinh). 2025 Oct 13. e06497

Disruption of Gut Microbiota-Mediated De Novo NAD+ Synthesis Contributes to the Development of Polycystic Ovary Syndrome.

Ke Chen, Huafeng Geng, Yang Zheng, Hongyang Xie, Rui Qin, Junyang Chen, Cong Ye.

  Polycystic ovary syndrome (PCOS) is a severe disorder that compromises female ovarian health and elevates the risk of various diseases, including endometrial cancer. The pathogenesis of PCOS remains poorly understood, which has hindered the development of effective interventions. In this study, it is demonstrated that patients with PCOS exhibit significant gut dysbiosis. FMT from PCOS patients (P-FMT) into mice induced PCOS-associated symptoms and histological alterations. Notably, both PCOS patients and P-FMT mice exhibit distinct metabolic profiles in the gut, suggesting a gut microbiota-mediated metabolic reprogramming. Furthermore, impaired tryptophan metabolism, particularly reduced levels of 3-hydroxyanthranilic acid (3-HAA), is observed in both PCOS patients and P-FMT mice. Administration of 3-HAA to mice alleviated DHEA-induced PCOS. Mechanistically, 3-HAA promoted NAD+ synthesis via the de novo biosynthesis pathway, thereby inhibiting DHEA-induced ferroptosis by modulating the mitochondrial DNA-cGAS-STING axis. Collectively, these findings reveal the critical role of gut microbiota-mediated NAD+ synthesis in the pathogenesis of PCOS, underscoring the potential of targeting gut microbiota and NAD+ homeostasis as a therapeutic strategy for PCOS prevention and management.

Keywords:  3‐HAA; NAD+; PCOS; ferroptosis; gut microbiota

DOI:  https://doi.org/10.1002/advs.202506497
Curr Opin Clin Nutr Metab Care. 2025 Oct 06.

The mitochondrial side of frailty.

Emanuele Marzetti, Rosa Di Lorenzo, Anna Picca.

   PURPOSE OF REVIEW: Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
RECENT FINDINGS: Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
SUMMARY: Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations.

Keywords:  inflammaging; metabolic dysregulation; mitochondrial quality control; oxidative capacity; physical frailty

DOI:  https://doi.org/10.1097/MCO.0000000000001175
Nutrients. 2025 Oct 02. pii: 3148. [Epub ahead of print]17(19):

Effects of Nicotinamide Mononucleotide Supplementation and Aerobic Exercise on Metabolic Health and Physical Performance in Aged Mice.

Yi-Ju Hsu, Mon-Chien Lee, Huai-Yu Fan, Yu-Ching Lo.

  Background/Objectives: Aging is characterized by progressive physiological and metabolic decline. Aerobic exercise mitigates age-related impairments, and nicotinamide mononucleotide (NMN), a precursor in the NAD+ salvage pathway, has emerged as a nutritional intervention to promote healthy aging. This study investigated whether NMN supplementation combined with aerobic exercise provides synergistic benefits on physical performance and metabolic regulation in aged mice. Methods: Forty male C57BL/6J mice, including eight young (8 weeks) and thirty-two aged (85 weeks) mice, were randomly assigned to five groups: young sedentary (YS), aged sedentary (AS), aged with exercise (AE), aged with NMN (ASNMN; 300 mg/kg/day), and aged with combined NMN and exercise (AENMN). Interventions lasted six weeks. Assessments included grip strength, muscle endurance, aerobic capacity, oral glucose tolerance test (OGTT), and indirect calorimetry, followed by biochemical and molecular analyses of NAMPT and SirT1 expression. Results: The AENMN group demonstrated significant improvements in maximal strength and aerobic endurance compared with the AS group (p < 0.05). Both NMN and exercise interventions increased blood NAMPT concentrations, with the highest levels observed in the AENMN group (p < 0.05). SirT1 expression was elevated in the ASNMN and AENMN groups relative to YS (p < 0.05). Glucose tolerance improved in the ASNMN and AENMN groups (p < 0.05). Enhanced energy metabolism in the AENMN group was indicated by increased oxygen consumption, elevated energy expenditure, and reduced respiratory quotient. Conclusions: NMN supplementation, particularly when combined with aerobic exercise, effectively improved aerobic performance, glucose regulation, and systemic energy metabolism in aged mice. These findings suggest that NMN, in synergy with exercise, may serve as a promising nutritional strategy to counteract age-associated metabolic and functional decline.

Keywords:  NAMPT; aerobic exercise; aging; energy metabolism; exercise performance; nicotinamide mononucleotide (NMN)

DOI:  https://doi.org/10.3390/nu17193148
Cell Stem Cell. 2025 Oct 14. pii: S1934-5909(25)00339-X. [Epub ahead of print]

Vitamin C conveys geroprotection on primate ovaries.

Ying Jing, Huifen Lu, Jingyi Li, Zan He, Liyun Zhao, Chen Zhang, Ziqi Huang, Lixiao Liu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Xiaobing Fu, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu.

  Ovarian aging plays a pivotal role in female reproductive health, with implications for treatment strategies and quality of life. However, the potential of a single pharmaceutical agent to mitigate primate ovarian aging remains largely unexplored. Our 3.3-year study in monkeys demonstrates that oral vitamin C has geroprotective effects against ovarian aging. Vitamin C diminishes key aging biomarkers, including oxidative stress and follicular depletion. Using a single-cell transcriptomic clock, we show that vitamin C can reduce the biological age of oocytes by 1.35 years and somatic cells by 5.66 years. This effect is partly mediated by the NRF2 pathway, which alleviates ovarian cell senescence and inflammation. Our findings highlight the role of vitamin C in combating primate ovarian aging and provide insights for developing interventions against human ovarian aging.

Keywords:  NRF2; aging; aging clock; antioxidant; inflammation; ovary; oxidative stress; primate; senescence; vitamin C

DOI:  https://doi.org/10.1016/j.stem.2025.09.008
J Neuroinflammation. 2025 Oct 15. 22(1): 235

cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives.

Huayu Li, Ruixin Cai, Yu Zhou, Yichen Jiang, Sijie Tan.

  Aging is a major risk factor for neurodegenerative diseases, yet the underlying mechanisms linking aging to neurodegeneration remain incompletely understood. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in sensing mislocalized cytoplasmic DNA, triggering innate immune responses such as type I interferon (IFN-I) and NF-κB signaling, and promoting senescence-associated secretory phenotypes (SASP). In the aging central nervous system (CNS), cellular senescence is accompanied by mitochondrial DNA (mtDNA) leakage, nuclear DNA damage, and other changes that may aberrantly activate the cGAS-STING pathway. This activation drives neuroinflammation, potentially increasing susceptibility to neurodegenerative diseases or exacerbating pre-existing pathology. Conversely, neurodegenerative disease-related processes-such as pathological protein aggregation-can further stimulate cGAS-STING signaling, amplifying inflammatory cascades and accelerating cellular senescence. This review explores the molecular mechanisms linking cGAS-STING activation to neurodegeneration and discusses potential therapeutic strategies targeting this pathway.

Keywords:  Aging; Microglia; Neurodegenerative diseases; Neuroinflammation; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12974-025-03563-8
Int J Mol Sci. 2025 Oct 09. pii: 9826. [Epub ahead of print]26(19):

Oxidative Stress, Mitochondrial Quality Control, Autophagy, and Sirtuins in Heart Failure.

Jan Krekora, Marcin Derwich, Jarosław Drożdż, Elzbieta Pawlowska, Janusz Blasiak.

  Heart failure (HF) has become an emerging problem, especially in regions where life expectancy is increasing. Despite its prevalence, the mechanisms behind HF development are not well understood, which is reflected in the lack of curative therapies. Mitochondria, autophagy, and sirtuins form a crucial triad involved in HF pathogenesis, interconnected by oxidative stress. Identifying a common pathway involving these three components could be valuable in developing new treatment strategies. Since HF is the end result of several cardiovascular diseases, this review highlights the main HF precursors and explores the roles of mitochondrial quality control (mtQC), autophagy, and sirtuins in HF development. Dysfunctional mitochondria may play a key role by enhancing oxidative stress and influencing autophagy and sirtuins, both of which possess antioxidant properties. The dual nature of autophagy-its pro-life and pro-death roles-may contribute to different outcomes in HF related to oxidative stress. As mtQC, autophagy, and sirtuins may interact, we present data on their mutual dependencies in HF. However, the specificity of these interactions remains unclear and needs further investigation, which could help identify new therapeutic targets. In conclusion, the interplay between mtQC, autophagy, and sirtuins may be crucial in HF pathogenesis and could be leveraged in developing HF treatments.

Keywords:  autophagy; heart failure; mitochondria; oxidative stress; sirtuins

DOI:  https://doi.org/10.3390/ijms26199826
Immunity. 2025 Oct 14. pii: S1074-7613(25)00427-3. [Epub ahead of print]58(10): 2362-2363

Burning the candle at both ends: ROS-mediated telomere damage drives T cell dysfunction.

Alexander J Wesolowski, Rahul Roychoudhuri.

T cells need reactive oxygen species (ROS) for activation and memory formation, yet excessive ROS can drive dysfunction. Rivadeneira et al. show that chronic T cell activation in tumors exposes telomeres to damaging mitochondrial ROS, contributing to T cell dysfunction.

DOI: https://doi.org/10.1016/j.immuni.2025.09.016
Endocr Metab Immune Disord Drug Targets. 2025 Oct 10.

Functions of Estrogen and Estrogen-Related Receptors in Diseases of the Female Reproductive System.

Jinzheng Wang, Ziming Zhu, Liding Fan, Weiyue Zhang, Fangyuan Li, Lin Liu, Letao Jing, Kai Meng, Jinxiang Yuan, Huali Zhang.

  Diseases of the female reproductive system are prevalent. These conditions often have a high proportion of asymptomatic patients and prolonged treatment durations. Estrogen, a crucial steroid hormone, plays a central role in most diseases of the female reproductive system. It is essential for promoting the development of reproductive organs and follicular growth, maintaining regular menstrual cycles, and supporting pregnancy. The expression levels of estrogen-related receptors and circulating estrogen levels are closely linked to various female reproductive disorders. However, most diseases of the female reproductive system lack specific therapeutic drugs, and estrogen therapy is still primarily used as a monotherapy. The clinical application of hormone-targeted therapies remains immature. In light of these challenges, this review focuses on the effects of estrogen and estrogen-related receptors on common diseases of the female reproductive system. This review provides an overview of the pathogenesis and therapeutic mechanisms of four common gynecological disorders: endometriosis (EMS), abnormal uterine bleeding (AUB), polycystic ovary syndrome (PCOS), and premature ovarian insufficiency (POI). This study aims to identify novel target receptors and provide insights for estrogen-based therapies in the treatment of diseases of the female reproductive system.

Keywords:  Estrogen; diseases of the female reproductive system; estrogen-related receptors; treatment of gynecological diseases.

DOI:  https://doi.org/10.2174/0118715303406667250915224123
Diabetologia. 2025 Oct 11.

Daily life stress is linked to increased glucose levels in individuals with insulin resistance: a real-world assessment.

Esther Schrems, Judith R Gruber, Carmen Schiweck, Alea Ruf, Andreas Reif, Rejane Goldbach, Sharmili Edwin Thanarajah, Silke Matura.

   AIMS/HYPOTHESIS: The bidirectional relationship between stress and diabetes is well documented, with chronic stress increasing the risk of diabetes onset and stress adversely affecting clinical outcomes in individuals with diabetes. However, the impact of daily life stress on glucose levels in insulin-resistant individuals, who are at risk of type 2 diabetes, remains unclear.
METHODS: The analysis included 116 participants (62 insulin-resistant [IR] and 54 insulin-sensitive [IS] participants) aged 18-78 years. Insulin resistance was defined by a HOMA-IR index above 2.5. Participants completed three standardised baseline questionnaires to assess their affective state. Using ambulatory assessment, daily life stress and affect were assessed for 3 days while continuous glucose monitoring was conducted for 7 days. Linear mixed-effect models were applied to estimate effects between parameters.
RESULTS: While perceived daily stress was not different between individuals with insulin resistance and control participants, we found a significant positive effect of stress on blood glucose level ( β^=6.24×10-3 , p=0.005) in IR individuals, but not in IS control participants. Additionally, stress levels predicted negative affect in both IR ( β^=-0.08, p<0.001) and IS ( β^=-0.08, p<0.001) participants.
CONCLUSIONS/INTERPRETATION: Daily life stress contributes to a significant increase in glucose levels in IR individuals, highlighting the need for tailored interventions to mitigate further deterioration and potential progression to type 2 diabetes. These results underscore the importance of integrating stress management strategies into diabetes prevention in at-risk populations. Ambulatory assessments can serve as monitoring tools for identifying at-risk individuals and for testing the efficacy of targeted interventions.
CLINICAL TRIAL REGISTRATION: Registered under https://drks.de/register/de , identifier no. DRKS00022774.

Keywords:  Ambulatory assessment; Blood glucose; Insulin resistance; Stress

DOI:  https://doi.org/10.1007/s00125-025-06552-x
Nutrients. 2025 Sep 30. pii: 3106. [Epub ahead of print]17(19):

Potential Therapeutic Effects of Oolong Tea Phytochemicals on NLRP3 Inflammasome Assembly and Oxidative Stress.

Ming-Shyan Wang, Szu-Nian Yang, Yi-Ping Chang, Chi-Sheng Wu, Hung-Chi Yang, Jia-Feng Chang.

   BACKGROUND/OBJECTIVES: Tea, the world's second most consumed beverage after water, contains diverse phytochemicals that have garnered growing interest for their potential ability to modulate inflammasome activation. This study examined the antioxidant and anti-inflammatory properties of oolong tea (OLT) extracts, with a specific focus on their regulatory effects on NLRP3 inflammasome assembly-a critical mediator in chronic inflammatory diseases.
METHODS: OLT extracts were prepared from the Jin-Xuan cultivar with quantification for bioactive components (total phenolics, flavonoids, condensed tannins, and proanthocyanidins). J774A.1 murine macrophages were primed with LPS and stimulated with ATP to induce inflammasome activation. Therapeutic potentials of OLT extracts were assessed by measuring cytokine secretion, expression of NLRP3 inflammasome-related proteins (NLRP3, ASC, Caspase-1, and IL-1β), inflammasome complex formation, and ROS generation via biochemical assays, immunoblotting, and fluorescence microscopy.
RESULTS: OLT extracts, particularly at 100 µg/mL, markedly suppressed both the priming and activation phases of NLRP3 inflammasome formation. OLT treatment reduced IL-1β secretion by more than 50%, attenuated ASC oligomerization and speck formation, inhibited caspase-1 cleavage, and lowered intracellular ROS levels by approximately 50%.
CONCLUSIONS: These findings suggest that OLT extracts exert potent anti-NLRP3 inflammasome activity and offer immunomodulation potential in preventing inflammation-related diseases such as infections, cancer, and neurodegenerative disorders. Further in vivo investigations, followed by clinical applications and epidemiological studies, are warranted to validate these preventive effects in human populations.

Keywords:  ASC; Caspase-1; IL-1β; NLRP3; ROS; oolong tea phytochemicals

DOI:  https://doi.org/10.3390/nu17193106
Mech Ageing Dev. 2025 Oct 15. pii: S0047-6374(25)00096-X. [Epub ahead of print] 112120

Morin enhances healthspan and neuroprotection in Caenorhabditis elegans via mitochondrial stress adaptation.

Yong-Ha Jo, Hyun-Ok Song, Dong-Sung Lee, Jeong Hoon Cho.

  Morin, a dietary flavonoid with antioxidant and metabolic activity, promotes healthy ageing in Caenorhabditis elegans. Morin extended lifespan by ~18% and alleviated age-related decline in neuronal integrity, locomotion, learning and memory, and intestinal fat accumulation. Mitochondrial potential was moderately decreased, suggesting mild uncoupler-like activity. Morin downregulated daf-2 and upregulated daf-16, accompanied by enhanced DAF-16::GFP nuclear localization, indicative of IIS/FOXO pathway activation. Gene expression profiling revealed modulation of mitochondrial stress-responsive (atfs-1, fmo-2), antioxidant (gst-4, hsf-1), and lipid metabolism (fat-6, fat-7) genes. Notably, pink-1 and pdr-1 expression increased, whereas morin's neuroprotective effects were abolished in pink-1; pdr-1 mutants, suggesting that its benefits may involve PINK-1/PDR-1-dependent mitophagy or mitochondrial quality control. Collectively, morin enhances stress resilience and mitochondrial homeostasis through IIS/FOXO-associated regulation, supporting its potential as a natural compound that promotes healthspan.

Keywords:  Caenorhabditis elegans; Mitophagy; healthspan; mitochondrial membrane potential; morin

DOI:  https://doi.org/10.1016/j.mad.2025.112120
Iran J Pharm Res. 2025 Jan-Dec;24(1):24(1): e164861

IDO Inhibition by 1-Methyltryptophan: Unlocking New Paths to Treat Ovarian Dysfunction and Hormonal Imbalance in PCOS.

Hediyeh Gheymoumi, Sevda Shayesteh, Marziyeh Amiri-Andebilib, Naim Gheymoumi, Fatemeh Sharifi, Ahmad Reza Dehpour.

   Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic inflammation, as well as metabolic and reproductive dysfunction. While insulin resistance affects many tissues, ovarian tissue exhibits insulin hypersensitivity, which promotes androgen excess and worsens PCOS symptoms. The kynurenine pathway (KP), a major route of tryptophan metabolism regulated by indoleamine 2,3-dioxygenase (IDO), is implicated in ovarian dysfunction in PCOS.
Objectives: To investigate the effects of IDO inhibition on ovarian morphology and insulin signaling in a PCOS rat model, evaluating its potential as a therapeutic approach compared to metformin.
Methods: Twenty-four female rats were randomly assigned to four groups: Control, PCOS, 1-methyltryptophan (1-MT, IDO inhibitor) (10 mg/kg), and metformin (100 mg/kg). The PCOS was induced by subcutaneous testosterone injections at 21 days of age. Outcomes measured included luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio, ovarian weight, follicle and corpus luteum counts, granulosa and theca layer thickness, fasting blood glucose, and ovarian expression of insulin receptor substrate 1 (IRS-1) and phosphoinositide 3-kinase (PI3K).
Results: The results indicated that both treatments, 1-MT and metformin, significantly reduced the LH/FSH ratio, with metformin showing a more substantial effect. Additionally, 1-MT increased ovarian weight and the number of healthy follicles (HFs), unlike metformin. Both treatments increased the number of corpora lutea (CL), indicating restored ovulation. The IRS-1 expression decreased with both treatments, whereas PI3K levels remained unchanged.
Conclusions: The IDO inhibition by 1-MT improves ovarian function and hormonal balance in PCOS more effectively than metformin, likely by reducing inflammation and modulating insulin signaling. These findings support 1-MT as a promising therapeutic candidate for PCOS management and improving ovarian function. However, these results are from a short-term animal study, and further clinical trials are necessary to assess long-term efficacy and safety.

Keywords:  1-Methyltryptophan; IRS-1 Protein; Indoleamine 2,3-Dioxygenase; Insulin; Polycystic Ovary Syndrome

DOI:  https://doi.org/10.5812/ijpr-164861
Neurosci Biobehav Rev. 2025 Oct 13. pii: S0149-7634(25)00420-8. [Epub ahead of print]179 106419

The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms.

D Parker Kelley, S Parker Singleton, Katy Venable, Gabriel Strum, Anna Skovgaard, Joseph Francis, Thomas C Neylan, Ellen R Bradley, Joshua Woolley, Martin Picard, Aoife O'Donovan.

  Psychiatric, cardiometabolic, and immune disorders are highly comorbid, and are precipitated by psychological stress. To explain why these conditions co-occur and how stress triggers their pathogenesis, we introduce the Allostatic Triage Model of Psychopathology (ATP Model) that explains psychopathogenesis, and these bidirectional associations through a bioenergetic lens. Stress increases the energy demand on biological systems, which operate on a finite energy budget, increasing the risk of energy scarcity, especially in the brain, which faces high energy needs and limited access to energetic resources. Allostatic processes anticipate stress-induced increases in energy demand and regulate systemic and brain energy allocation from mind-to-mitochondria, a process that we call "allostatic triage". The brain allostatic-interoceptive system generates internal models of systemic and brain metabolism and energy output that are used to produce affective states, which regulate allostasis. In turn, we propose that affect regulates allostatic triage among functional brain networks. Chronic and traumatic stress dysregulates the mitochondrial and brain networks that regulate affect by reducing metabolic efficiency. We propose that stress-induced energy scarcity and affective dysregulation exacerbates allostatic triage to the networks most necessary for short-term survival, at the expense of non-vital processes contributing to long-term optimization and well-being, dysregulating allostasis and driving transdiagnostic disease pathogenesis. Persistent network activation patterns underlying psychiatric symptoms can then become entrenched as psychiatric disorders through activity-dependent neuroplasticity, also known as canalization. Altogether, we propose that stress dysregulates mitochondria, affect, and allostatic triage, impairing allostasis, and driving transdiagnostic pathological states, which are canalized over time into transdiagnostic disease.

Keywords:  Affect; Allostasis; Allostatic Load; Allostatic Triage; Canalization; Mitochondria; Psychopathology

DOI:  https://doi.org/10.1016/j.neubiorev.2025.106419
Nat Metab. 2025 Oct 13.

NAD+ precursor supplementation in human ageing: clinical evidence and challenges.

Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.

DOI: https://doi.org/10.1038/s42255-025-01387-7
Nature. 2025 Oct 13.

Men's brains shrink faster than women's: what that means for Alzheimer's.

Rachel Fieldhouse.



Keywords:  Ageing; Brain; Neurodegeneration

DOI:  https://doi.org/10.1038/d41586-025-03353-5
Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00399-4. [Epub ahead of print]87 103886

Quercetin ameliorates oxidative stress in BMP15-deficient oocytes by regulating the ERK1/2-GSK3β-CypD pathway.

Yafei Jiao, Xinran Li, Jinming Guo, Chang Bei, Xintong Jiang, Houwu Jiang, Bingqian Mi, Tiantuan Jiang, Xiaohong Liu, Yaosheng Chen, Peiqing Cong, Zuyong He.

  Bone morphogenetic protein 15 (BMP15) is an oocyte-secreted growth factor, which interacts with ovarian follicular somatic cells and in turn promotes oocyte maturation. Disrupting BMP15 by CRISPR-ctRNP has been found to severely impair in vitro maturation (IVM) of porcine oocytes, accompanied with mitochondrial dysfunction and increased accumulation of reactive oxygen species (ROS). To investigate whether the plant-derived antioxidant quercetin (QUE) is able to rescue the IVM of BMP15-deficient oocytes, porcine oocytes microinjected with CRISPR-ctRNP targeting BMP15 were treated with 10 μM QUE, and we found that QUE can effectively rescue the impaired IVM of BMP15-deficient oocytes by restoring the impaired mitochondrial functions and reducing ROS through activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Activated ERK1/2 in turn inactivated glycogen synthase kinase-3β (GSK3β), which subsequently reduced Cyclophilin D (CypD) levels, and probably modulated the status of the permeability transition pore (PTP) of mitochondria, contributing to the reduced oxidative stress and apoptosis in porcine oocytes, and thus the improved oocyte quality and IVM. Our study further revealed the molecular mechanisms of QUE on alleviating oxidative stress of BMP15-deficient oocytes, suggesting that QUE may be a promising candidate for improving quality of oocytes with BMP15 mutations.

Keywords:  BMP15-Deficiency; ERK1/2 signaling pathway; Mitochondrial function; Quercetin; ROS

DOI:  https://doi.org/10.1016/j.redox.2025.103886
Nutr Res Pract. 2025 Oct;19(5): 664-681

Anti-fatigue and antioxidative effects of amino acid (Leu, Gln, Cys)-EGCG complex via NRF2 and PGC-1α pathways: insights from cellular, animal, and pilot clinical studies.

Sang Min Kim, Hyung Joo Suh, Woncheol Lee, Byoungkwon Kim, Sung Hee Han, Eun Young Jung, Yeok Boo Chang.

   BACKGROUND/OBJECTIVES: Fatigue is closely associated with an impaired mitochondrial function, oxidative stress, and inefficient energy metabolism, all contributing to reduced physical performance. Nutritional strategies targeting mitochondrial biogenesis and antioxidant defense may help alleviate fatigue and enhance endurance. This study examined the anti-fatigue and antioxidant effects of an amino acid (AA)-epigallocatechin gallate (EGCG) mixture comprised of 3 AAs (cysteine [Cys], glutamine [Gln], and leucine [Leu]) and EGCG on mitochondrial biogenesis, oxidative stress mitigation, and physical performance enhancement.
MATERIALS/METHODS: C2C12 myoblasts were treated to assess mitochondrial biogenesis-related gene expression and oxidative stress markers. Animal studies measured the swimming endurance, glycogen, adenosine triphosphate (ATP), and serum parameters. A pilot clinical trial evaluated the blood glucose, lactate, and serum enzyme levels post-exercise.
RESULTS: In cellular experiments, a 1:1:3 ratio of the AA mixture (Cys, Gln, and Leu) with EGCG enhanced mitochondrial biogenesis-related gene expression (AMP-activated protein kinase, sirtuin 1, and peroxisome proliferator-activated receptor gamma coactivator 1α [PGC-1α]) and reduced the oxidative stress markers (reactive oxygen species and malondialdehyde [MDA]). Animal studies revealed significant increases in swimming endurance, elevated glycogen and ATP levels, and reduced serum fatigue markers (creatine phosphokinase, lactate dehydrogenase, and blood nitrogen). Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) and PGC-1α expression was significantly upregulated in the gastrocnemius muscle, supporting enhanced mitochondrial function. In addition, the antioxidant effects were observed with reduced MDA levels in liver tissue. Clinical trial data showed improved blood lactate clearance and higher post-exercise blood glucose levels in the AA-EGCG group compared to the placebo group.
CONCLUSION: The AA-EGCG mixture enhances mitochondrial biogenesis and antioxidant capacity by activating the NRF2 and PGC-1α pathways, improving physical performance and reducing fatigue. This study highlights its potential as a supplement for managing fatigue and enhancing endurance.

Keywords:  amino acids; antioxidants; catechin; fatigue; leucine

DOI:  https://doi.org/10.4162/nrp.2025.19.5.664
Am J Physiol Gastrointest Liver Physiol. 2025 Oct 17.

Sex Dimorphism and Substrate Dependency of Liver Mitochondrial Bioenergetics and H2O2 Production.

Devanshi D Dave, Pardis Taheri, Sri Rahavi Boovarahan, Joohyun Kim, Allen W Cowley, Said H Audi, Ranjan K Dash.

  Mitochondrial bioenergetics and H2O2 production play a central role in maintaining liver metabolic function and redox balance. Understanding sex dimorphism and substrate dependency in these mitochondrial processes is crucial for elucidating the regulatory mechanisms that govern male vs. female differences in liver physiology in health and disease. This study aimed at investigating sex-specific and substrate-dependent alterations in liver mitochondrial respiratory rates (JO2), membrane potential (ΔΨ), and H2O2 production and their metabolic regulation. Liver mitochondria were isolated from adult male and female Sprague-Dawley (SD) rats. Four substrate combinations-pyruvate+malate (PM), glutamate+malate (GM), succinate, and succinate with complex I inhibitor rotenone (SR)-were used to determine their impact on the activities of the electron transport chain (ETC) and TCA cycle complexes. ADP was added to determine the influence of substrates on oxidative phosphorylation (OxPhos). JO2 and ΔΨ were measured simultaneously using an Oroboros Oxygraph-2k respirometer with the cationic rhodamine dye TMRM. H2O2 production was measured spectrofluorometrically using the Amplex Red and Horseradish Peroxidase assay. Our results show that male and female liver mitochondria displayed distinct respiratory patterns for different substrates. GM and succinate yielded higher JO2, while PM yielded the lowest JO2. Notably, female mitochondria exhibited higher JO2 than males across all substrates. Both ΔΨ and H₂O₂ production showed substrate-dependent patterns, with females exhibiting higher values than males across all substrates. These findings reveal sex-specific differences in liver mitochondrial function, driven by substrate-dependent engagement of the ETC and TCA cycle complexes towards OxPhos, with females showing higher respiratory capacity and H2O2 production.

Keywords:  Mitochondrial bioenergetics; Oxidative phosphorylation; Oxidative stress; Reactive oxygen species; Sex differences

DOI:  https://doi.org/10.1152/ajpgi.00196.2025