bims-mistre 2026-10-11 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–10–11
fourteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Longer lipids mark aging and constrain lifespan.
Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.
Betaine supplementation modulates mitochondrial and redox-related adaptations in premenopausal women with overweight: a randomized controlled trial.
Enhanced bioavailability and short-term safety of a micellar green tea extract formulation co-delivered with N-acetylcysteine: a randomized crossover study in healthy adults.
Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.
The effects of chronic beetroot juice supplementation with resistance training on skeletal muscle mitochondrial and redox markers in middle-aged and older adults.
Coordinated mitochondrial quality control underlies oxidative stress resilience in MUSE stem cells.
Supraphysiological ascorbic acid infusion attenuates cerebrovascular dysfunction in middle-aged and older adults.
Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.
Polyethylene Microplastics and Cardiometabolic Mitochondrial-Redox Dysfunction in Preclinical Rodent Models: A Systematic Review and Meta-Analysis of Bioenergetic and Oxidative Stress Outcomes Across Target Organs.
Ergothioneine promotes functional recovery after spinal cord injury by stabilizing VPS35 to suppress mitochondrial damage-driven neuroinflammation and oxidative stress.
Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.
Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity: A Randomized Clinical Trial.
Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.

Nat Aging. 2026 Oct 06.

Longer lipids mark aging and constrain lifespan.

Weisha Li, Bauke V Schomakers, Maria M Trętowicz, Laura Hartshorne, Jonathan Sulc, Helgi I Ingólfsson, Tugba N Ozturk, Rob Ofman, Luc Legon, Kasandra Ippel, Michel van Weeghel, Martin A T Vervaart, Eric J M Wever, Simone W Denis, Signe Mosegaard, Adriana S Passadouro, Arwen W Gao, Hans R Waterham, Joris Hoeks, Patrick Schrauwen, Gajja S Salomons, Evan G Wiliams, Paul M L Janssen, Vincent A J Warnaar, Linda Partridge, Johan Auwerx, Sebastian Grönke, Mirre J P Simons, Jolanda van der Velden, Frédéric M Vaz, Riekelt H Houtkooper, Georges E Janssens.

Aging drives molecular changes that impair cellular and tissue function. Lipids are central to membrane structure, signaling and energy storage, yet their remodeling during aging remains unclear. Here, using cross-species, multi-tissue lipidomics, we identify elongation of lipid acyl chains as a conserved hallmark of aging across mice, Caenorhabditis elegans, Drosophila and humans. Similar lengthening occurs during the progression of human heart disease, whereas dietary restriction shortens cardiac lipids in mice. Integrated analyses reveal that aging is characterized by a shift toward longer lipids accompanied by depletion of shorter species, indicating ratiometric remodeling. Following this, we identify the lipid remodeler Plb1 as a regulator of this process, with expression correlating with lifespan in mice and genetic analyses supporting a causal role in human frailty. In C. elegans, Plb1 knockdown reverses lipid elongation and extends lifespan in a lipid-length-dependent manner. Together, these findings establish lipid chain length remodeling as a conserved, actionable hallmark of aging.

DOI: https://doi.org/10.1038/s43587-026-01223-x
Front Nutr. 2026 ;13 1865556

Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health.

Wu Zhang.

  Aging and neurodegenerative disorders (NDDs) are intricately linked to a gradual deterioration in nicotinamide adenine dinucleotide (NAD+) metabolism, compromised mitochondrial functionality, persistent inflammation, and modified gut-brain interactions. Derivatives of vitamin B3, such as niacin, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, have been identified as pivotal NAD+ precursors that possess the potential to support cellular bioenergetic processes and modulate pathways associated with brain aging. Evidence from preclinical studies and emerging clinical investigations suggests that NAD+-enhancing interventions may improve mitochondrial function and modulate neuroinflammatory pathways, thereby supporting cellular processes involved in synaptic plasticity and cognitive function; however, their long-term efficacy and clinical relevance in NDDs remain to be fully established. Concurrently, physical exercise serves as a robust physiological stimulus that augments NAD+ biosynthesis, modulates hypoxia-inducible factor-1α-dependent adaptive responses, fosters neurotrophic signaling, and enhances both vascular and metabolic health of the brain. Furthermore, emerging evidence suggests that the gut microbiota directly contributes to NAD+ homeostasis by regulating vitamin B3 precursor availability, tryptophan metabolism, and host metabolic signaling, while also influencing the efficacy of NAD+-enhancing interventions, thereby affecting systemic inflammation, metabolic equilibrium, and the production of neuroactive metabolites. Collectively, the interaction among vitamin B3 supplementation, physical activity, and gut microbiota may represent a promising framework for investigating strategies aimed at supporting cognitive health and brain resilience during aging, although definitive therapeutic applications require further validation. This review integrates current molecular, preclinical, and clinical evidence to establish mechanistic links between NAD+ metabolism, brain aging, cognitive dysfunction, and neurodegeneration, while emphasizing current limitations and future translational challenges associated with combining vitamin B3 metabolites, exercise, and microbiome-targeted approaches.

Keywords:  NAD+ repletion; brain aging; exercise; gut microbiome dynamics; neurodegenerative disease; vitamin B3 metabolites

DOI:  https://doi.org/10.3389/fnut.2026.1865556
Eur J Nutr. 2026 Oct 07. pii: 275. [Epub ahead of print]65(8):

Betaine supplementation modulates mitochondrial and redox-related adaptations in premenopausal women with overweight: a randomized controlled trial.

Emilia Zawieja, Monika Młodzik-Czyżewska, Agata Chmurzynska.

   BACKGROUND & AIMS: The aim of this study was to investigate the effects of betaine supplementation on mitochondrial and redox-associated parameters in premenopausal women with overweight or obesity. We hypothesized that betaine enhances selected mitochondrial enzyme content and improves antioxidant defense.
METHODS: In this randomized controlled trial, premenopausal women with overweight or obesity were assigned to receive anhydrous betaine supplementation (3 g/d) or a placebo condition for eight weeks. Mitochondrial enzyme content was assessed in peripheral blood mononuclear cells (PBMCs), including citrate synthase (CS) and cytochrome c oxidase (COX). Redox-related parameters were evaluated in plasma; these included the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as oxidized glutathione (GSSG) concentration. Preintervention and postintervention measurements were compared between groups.
RESULTS: A significant treatment × time interaction was observed for CS concentration in PBMCs (p = 0.043). The pre-to-post change differed significantly between the betaine and placebo groups (between-group difference in change: 102.3 μg/mg protein, 95% CI 3.19 to 201.4), although the within-group pre-post changes were not statistically significant. No significant treatment × time interaction was observed for COX (p = 0.326). Plasma CAT activity showed a significant treatment × time interaction (p = 0.003, ηp2 = 0.213) and increased significantly only in the betaine group. No significant effects were observed for SOD (p = 0.825), GPx (p = 0.359), or GSSG (p = 0.693).
CONCLUSIONS: Betaine supplementation may selectively influence PBMC mitochondrial-associated parameters and circulating antioxidant enzyme activities in premenopausal women with overweight or obesity. The differential change in CS between the betaine and placebo groups and the increase in plasma CAT activity warrant further investigation, particularly to determine their physiological significance and underlying mechanisms.
TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT06344377.

Keywords:  Antioxidant enzymes; Betaine; Mitochondrial function; Overweight females; PBMC

DOI:  https://doi.org/10.1007/s00394-026-04131-3
Front Nutr. 2026 ;13 1940156

Enhanced bioavailability and short-term safety of a micellar green tea extract formulation co-delivered with N-acetylcysteine: a randomized crossover study in healthy adults.

Yiming Zhang, Afoke Ibi, Yun Chai Kuo, Peony Do, Min Du, Yoon Seok Roh, Roland Gahler, Mary Hardy, Simon Wood, Chuck Chang, Julia Solnier.

   Introduction: Green tea catechins, particularly epigallocatechin gallate (EGCG), the principal polyphenol in green tea (Camellia sinensis), possess diverse bioactivity but suffer from poor absorption and rapid metabolism, leading to very limited oral bioavailability. To address these challenges, this study investigated the pharmacokinetics, safety, and tolerability of LipoMicel® GTNAC® (LGT), a novel lipid-based green tea extract formulation co- delivered with N-acetylcysteine (NAC), compared with a standard green tea formulation (SGT) in healthy adults.
Methods: The study comprised two parts: a randomized, double-blind, crossover pharmacokinetic trial in 16 healthy adults comparing LGT 330 mg with SGT 330 mg and SGT 660 mg, followed by a 30-day open-label, single-arm safety study evaluating LGT 1,320 mg/day in 13 participants.
Results: For EGCG, LGT significantly increased baseline-adjusted systemic exposure compared with dose-matched SGT, producing a 4.2-fold higher iAUC₀-₂₄ (1857 ± 1,479 vs. 443 ± 1,570 ng·h/mL; p = 0.032) and a 3.0-fold higher iCmax (267 ± 235 vs. 88.6 ± 60.0 ng/mL; p = 0.037). No clinically significant adverse events or clinically meaningful changes in blood chemistry were observed during the 30-day safety phase.
Conclusion: These findings demonstrate that LGT significantly enhances systemic EGCG exposure while remaining well tolerated for over 30 days in healthy adults. Larger and longer-term studies are warranted to determine whether improved EGCG exposure translates into clinically meaningful health benefits.
Clinical trial registration: https://clinicaltrials.gov/, registration number NCT06971536.

Keywords:  GTNAC; LipoMicel; N-acetylcysteine; bioavailability; catechins; epigallocatechin gallate; green tea extract; lipid-based delivery

DOI:  https://doi.org/10.3389/fnut.2026.1940156
Aging Cell. 2026 Oct;25(10): e70703

Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline.

Hamsa Vardini Senthil Kumar, Debanik Choudhury, Pedro Lei, Pihu Mehrotra, Shahryar Shahini, Sydney Swedick, John Toftegaard, Stelios T Andreadis.

Age-associated loss of skeletal muscle mass and function, also known as sarcopenia, is closely linked to mitochondrial dysfunction. In this study, we report that senescent skeletal muscle myoblasts exhibit elevated activity and expression of the enzyme glutaminase (GLS1), which is mediated by p38 MAPK signaling and leads to intracellular urea accumulation that impairs mitochondrial function. Pharmacological inhibition of GLS1 with CB-839 reduced urea levels, restored the expression of electron transport chain (ETC) complexes, and improved mitochondrial function. Consistent with our in vitro findings, CB-839 administration to progeroid mice similarly upregulated ETC complexes and enhanced mitochondrial respiratory capacity in skeletal muscle, leading to improved structural integrity and enhanced muscle strength. Together, these findings suggest that targeting glutamine metabolism via GLS1 inhibition may represent a promising therapeutic strategy to ameliorate age-related skeletal muscle decline by restoring mitochondrial health.

DOI: https://doi.org/10.1111/acel.70703
Eur J Appl Physiol. 2026 Oct 03.

The effects of chronic beetroot juice supplementation with resistance training on skeletal muscle mitochondrial and redox markers in middle-aged and older adults.

Breanna J Mueller, Mason C McIntosh, Dakota R Tiede, Derick A Anglin, George J Kontos, Dustyn T Lewis, Michael D Goodlett, Andrew D Frugé, Christopher B Mobley, Robert L Judd, Darren T Beck, Michael D Roberts, Andreas N Kavazis.

   PURPOSE: Acute nitrate-rich beetroot juice (BRJ) supplementation has been shown to improve aspects of endurance exercise performance. These effects may, in part, be due to nitric oxide-mediated effects on skeletal muscle contractility and mitochondrial function. However, no studies have investigated the effects of chronic BRJ supplementation with resistance training (RT) on molecular markers of mitochondrial adaptation and redox state within the skeletal muscle of older adults. Likewise, whether supplementation affects functional outcomes in this population is unresolved.
METHODS: In the current study, 27 older adults (56 ± 7 years old, 85.9 ± 20.6 kg, 36.1 ± 8.3% body fat) were block-randomized to consume either a nitrate-depleted (Placebo) or nitrate-rich (~ 13 mmol) BRJ daily and complete 12 weeks of supervised total body RT (2 days per week). Vastus lateralis (VL) biopsies and measurements of leg extensor peak force, strength-endurance, and fatigue were obtained prior to training and ~72 h following the last training bout.
RESULTS: In all participants, RT increased VL citrate synthase activity (i.e., mitochondrial content), certain proteins indicative of mitochondrial biogenesis and dynamics, and most leg extensor performance variables. However, BRJ supplementation did not confer additional benefits with any of the outcomes.
CONCLUSIONS: RT in middle-aged and older adults dynamically alters muscle mitochondrial markers and knee extensor performance variables, albeit increased dietary BRJ consumption does not confer additional benefits.

Keywords:  Mitochondria; Nitrate supplementation; Older adults; Redox state; Resistance training; Skeletal muscle

DOI:  https://doi.org/10.1007/s00421-026-06460-x
Redox Rep. 2026 Dec 31. 31(1): 2698189

Coordinated mitochondrial quality control underlies oxidative stress resilience in MUSE stem cells.

Domenico Aprile, Sura Hilal Ahmed Al-Sammarraie, Alessia Ambrosino, Mohd Shahzaib, Yesuf Siraj, Afshin Samiminemati, Nicola Alessio, Gianfranco Peluso, Giovanni Di Bernardo, Umberto Galderisi.

   BACKGROUND: Reactive oxygen species (ROS) regulate stem-cell function, but sustained exposure causes oxidative damage, mitochondrial dysfunction and exhaustion. Multilineage-differentiating Stress-Enduring (MUSE) cells, a rare SSEA-3⁺ MSC subset, tolerate ROS-rich environments, although the mechanisms remain unclear.
METHODS: We compared MUSE, Non-MUSE (SSEA-3⁻) and MSCs after H₂O₂ exposure, assessing ROS clearance, mtDNA integrity, 8-oxo-dG, antioxidant and BER responses, mitochondrial morphology/function, mitophagy and biogenesis, with focus on the PGC-1α/NRF2 axis. Three independent biological replicates were analyzed by imaging, qPCR, flow cytometry and biochemical assays.
RESULTS: MUSE cells showed greater resistance to oxidative stress than MSCs and Non-MUSE cells. After H₂O₂, they displayed lower ROS accumulation (~15-25%), preserved mtDNA integrity, reduced 8-oxo-dG, rapid induction of antioxidant and BER-related genes, and maintenance of mitochondrial morphology, membrane potential and respiratory activity. MUSE cells also showed enhanced mitophagy, with >2-fold increased LAMP1-MitoTracker colocalization and induction of PINK1/phospho-Ub-S65, together with increased biogenesis, including ~45% higher COX-I/SDHA ratio, TFAM induction and PGC-1α activation at 48 h.
CONCLUSION: MUSE cells coordinate antioxidant defense, DNA repair, mitophagy and biogenesis through a remove-and-replace program that preserves mitochondrial function during oxidative stress.

Keywords:  MUSE stem cells; NRF2; PGC-1α; mitochondrial DNA damage; mitochondrial biogenesis; mitochondrial quality control; mitophagy; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1080/13510002.2026.2698189
Physiol Rep. 2026 Oct;14(19): e71120

Supraphysiological ascorbic acid infusion attenuates cerebrovascular dysfunction in middle-aged and older adults.

Theodore M DeConne, Faria Sanjana, Elizabeth M Habash, Kevin P Decker, Wendy Nichols, Joshua C Hobson, Nicholas A Rizzi, Christopher R Martens.

  Cerebrovascular endothelial function can be assessed by measuring the shear-mediated dilation or cerebrovascular reactivity (CVR) of the internal carotid artery (ICA) in response to transient hypercapnia (30 s). ICA CVR is blunted with aging; however, it is not known whether age-related reductions in ICA CVR are influenced by antioxidant-responsive mechanisms. The purpose of this study was to determine whether infusion of the antioxidant, ascorbic acid (AA) restores ICA CVR in middle-aged and older (MA/O) adults. We also examined the effect of AA on middle cerebral artery (MCA) CVR to sustained (3-min) hypercapnia. We hypothesized that MA/O adults would exhibit lower cerebrovascular function compared to young (Y) adults, and that infusion of AA would improve cerebrovascular function in MA/O adults, whereas infusion of saline (SAL) would not. The primary analytic sample included nine Y adults (25 ± 2 years) and nineteen (65 ± 6 years) MA/O adults, with analyzable data varying by outcome. ICA CVR was measured using high-resolution duplex ultrasound, and MCA CVR was measured using transcranial Doppler ultrasound. AA infusion improved ICA CVR and MCA CVR in MA/O adults but had no effect in Y adults. These findings suggest that age-related impairments in cerebrovascular function may be partly attributable to mechanisms responsive to acute, supraphysiological AA administration.

Keywords:  aging; antioxidant; cerebral blood flow; cerebrovascular function; endothelial function

DOI:  https://doi.org/10.14814/phy2.71120
Biogerontology. 2026 Oct 03. pii: 171. [Epub ahead of print]27(5):

Mechanistic reprogramming of the mtDNA-cGAS-STING axis in cellular senescence: from mitochondrial homeostatic disruption to inflammatory and immune outcomes.

Yapei Zhang, Jianing Zhu, Lifan Cui, Sirong Chen, Xin Li, Liwenqin Gao, Xin Chen, Kaizhi Wen, Binbin Zeng, Yayun Qian.

  In addition to cell cycle arrest, cellular senescence is characterized by disrupted mitochondrial homeostasis, development of the senescence-associated secretory phenotype (SASP), and alterations in the immune microenvironment. Mitochondrial membrane damage, disrupted mitochondrial dynamics, and impaired mitochondrial quality control (MQC) can occur during cellular senescence. These changes may cause mitochondrial DNA (mtDNA) to leak abnormally into the cytosol. Cytosolic mtDNA can then activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Unlike the acute innate immune response elicited by pathogen-derived DNA, cGAS-STING signaling in senescent cells is mainly activated by the aberrant cytosolic accumulation of endogenous DNA. This signaling activates the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) axis and induces a type I interferon response. It also promotes nuclear factor kappaB (NF-κB)-mediated inflammatory transcription, sustains the SASP, and modulates paracrine signaling and immune cell function. This review focuses on mitochondrial structural damage, mtDNA release, and impaired MQC. It summarizes the mechanisms that activate the mtDNA-cGAS-STING axis during cellular senescence and examines its functional changes. It also discusses the potential development of senescence-associated biomarkers. Current evidence suggests that this signaling axis mainly contributes to the maintenance and amplification of the inflammatory senescence phenotype. It is unlikely to independently determine the onset of cellular senescence. Its effects are highly dependent on cell type and pathological context, while assay standards, causal relationships, and therapeutic windows require further clarification.

Keywords:  CGAS-STING; Cellular senescence; Immunomodulation; Inflammatory senescence; Mitochondrial DNA; SASP

DOI:  https://doi.org/10.1007/s10522-026-10515-z
Cardiovasc Toxicol. 2026 Oct 09. pii: 126. [Epub ahead of print]26(11):

Polyethylene Microplastics and Cardiometabolic Mitochondrial-Redox Dysfunction in Preclinical Rodent Models: A Systematic Review and Meta-Analysis of Bioenergetic and Oxidative Stress Outcomes Across Target Organs.

Samuel Abiodun Kehinde, Wai Phyo Lin, Pinanong Na-Phatthalung, Siriwan Kantisin, Saira Naz, Mariana Teles Pereira, Sasitorn Chusri.

  Polyethylene microplastics (PE-MPs), the most globally abundant plastic polymer, accumulate in rodent tissues following experimental exposure and have been implicated in multi-organ biochemical disruption. Whether mitochondrial bioenergetic failure and redox collapse represent a convergent, organ-transcendent mechanism of PE-MP toxicity has not been quantitatively established. We conducted a PRISMA 2020-guided systematic review and random-effects meta-analysis, searching four electronic databases for controlled rodent studies reporting oxidative phosphorylation enzyme activities and redox markers following PE-MP exposure. Risk of bias was evaluated with SYRCLE, and evidence certainty was graded using a preclinical adaptation of GRADE. Thirteen studies (160 experimental arms, seven organ systems) met inclusion criteria; four studies across five organs supplied quantitative TCA cycle and electron transport chain data for the primary analysis, while the remaining nine contributed redox biomarker data. PE-MPs produced large, significant suppression of all four TCA cycle enzymes (CS: g = -2.69 to -3.82; p ≤ 0.009) and electron transport chain Complexes I, III, and IV (g = -3.08 to -3.70; p < 0.0001); Complex II showed non-significant, organ-specific adaptive upregulation. Pro-oxidant markers MDA and NO rose significantly, with NO showing near-perfect cross-organ homogeneity (I2 = 4.5%). Antioxidants GSH, SOD, and CAT were markedly depleted (g = -2.48, -2.93, -3.86; p < 0.0001). After mandatory GRADE/OHAT downgrades for unclear allocation concealment and single-group data dominance, certainty was Low for ten outcomes and Very Low for six. PE-MPs elicits the potency of being a mitochondrial toxicant via coherent tripartite axis throttling of TCA cycle, electron-leak amplification of the electron transport chain, and peroxynitrite-driven antioxidant exhaustion converging across renal, cardiac, pulmonary, neural, and gonadal tissues, with cardiac and cardiopulmonary mitochondrial injury emerging as a particularly consequential. These findings establish the mitochondrial-redox axis as a defining biochemical fingerprint of PE-MP multi-organ toxicity and provide mechanistic grounding for microplastic-associated cardiovascular risk.

Keywords:  Electron transport chain; Meta-analysis; Mitochondrial dysfunction; Multi-organ toxicity; Oxidative stress; Polyethylene microplastics; Redox imbalance; TCA cycle

DOI:  https://doi.org/10.1007/s12012-026-10203-x
Free Radic Biol Med. 2026 Oct 03. pii: S0891-5849(26)01162-7. [Epub ahead of print]257 188-204

Ergothioneine promotes functional recovery after spinal cord injury by stabilizing VPS35 to suppress mitochondrial damage-driven neuroinflammation and oxidative stress.

Jian Zhou, Chaoqiang Zhang, Yanan Zhang, Mingjie Xia, Zhanyang Qian, Guanhua Xu.

   BACKGROUND: Spinal cord injury (SCI) triggers a complex secondary injury cascade involving neuroinflammation, oxidative stress, and mitochondrial dysfunction. These interconnected pathological processes exacerbate neuronal damage and hinder functional recovery. However, effective therapeutic strategies targeting these interrelated pathways remain limited. Ergothioneine (EGT), a naturally occurring antioxidant with potent cytoprotective properties and a favorable safety profile, has emerged as a promising candidate for SCI intervention, yet its mechanisms of action in this context remain unclear.
METHODS: A mouse model of contusive SCI was established to evaluate the neuroprotective potential of ergothioneine. Mice received a moderate contusion injury at the T10 spinal segment by using a weight-drop impactor (5 g × 5 cm). Animals were randomly divided into four groups (n = 6 per group): Sham, SCI + vehicle, SCI+50 mg/kg EGT, and SCI+100 mg/kg EGT, with EGT administered intraperitoneally for 7 consecutive days starting at 6 h post-injury. Functional recovery was assessed using behavioral tests, histological analyses, and electrophysiological recordings. Proteomic profiling, limited proteolysis-mass spectrometry (LiP-MS), molecular docking, and molecular dynamics simulations were employed to identify direct molecular targets of ergothioneine. In vitro studies using LPS-stimulated BV-2 microglia were conducted to investigate its effects on mitochondrial function, oxidative stress, and inflammatory responses. VPS35 knockdown experiments were performed to validate its mechanistic involvement.
RESULTS: Ergothioneine treatment, particularly at 100 mg/kg, significantly improved locomotor recovery, preserved tissue integrity, and enhanced electrophysiological function in SCI mice. It markedly suppressed microglia-mediated neuroinflammation and oxidative stress, as indicated by reduced pro-inflammatory cytokine expression and decreased reactive oxygen species (ROS) production. Mechanistically, VPS35 was identified as a direct binding target of ergothioneine. Ergothioneine stabilized VPS35 expression, maintained mitochondrial membrane potential, reduced mitochondrial ROS generation, and alleviated mitochondrial dysfunction in activated microglia. Notably, VPS35 knockdown significantly attenuated these protective effects, demonstrating that ergothioneine exerts its actions in a VPS35-dependent manner.
CONCLUSION: Our study demonstrates that EGT confers neuroprotection after SCI by targeting VPS35, stabilizing mitochondria, and suppressing microglia-driven neuroinflammation and oxidative damage. These findings nominate EGT as a promising, well-tolerated therapeutic candidate for translational SCI treatment.

Keywords:  Ergothioneine; Microglia; Mitochondrial function; Neuroinflammation; Oxidative stress; Spinal cord injury; VPS35

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.011
Free Radic Biol Med. 2026 Oct 07. pii: S0891-5849(26)01182-2. [Epub ahead of print]257 224-240

Mitochondrial oxidative stress in skeletal muscle alters metabolic signaling responses to acute muscle contraction.

Ethan L Ostrom, Aurora Mattson-Hughes, James MacDonald, Theo Bammler, Nicholas J Day, Matthew J Gaffrey, Jesse B Trejo, Wei-Jun Qian, Bo Hagy, Jennifer R Giorgione, Kenneth M Humphries, Holly Van Remmen, Ricard Rodriguez-Mias, Judit Villen, David J Marcinek.

Activation of redox-sensitive signal transduction cascades is an increasingly appreciated mechanism of exercise adaptation in skeletal muscle. Aging and disease are associated with altered redox homeostasis, potentially altering redox responses to muscle contraction, and adaptations to exercise. It is unclear how chronic steady-state changes in redox homeostasis affect contraction-induced signaling cascades. Here we use a novel model of inducible superoxide dismutase 2 knockdown (iSOD2 KD) in skeletal muscle to test how chronic mitochondrial redox perturbations affect subsequent signaling responses to acute fatiguing muscle contraction. After a 12-week doxycycline treatment to knock down SOD2, littermate controls (CON) and iSOD2 KD animals underwent a single acute fatiguing contractile stimulus of the right hindlimb. Muscle tissue was collected immediately after or 3 h after completion of the stimulus followed by redox proteomic and transcriptomic analysis, respectively, and compared to naïve unstimulated controls of each genotype. iSOD2 KD led to decreased protein expression of several key iron-sulfur cluster biosynthesis proteins and increased reversible thiol oxidation of proteins in the mitochondrial compartment in response to muscle contraction. The transcriptomic response to contraction in KD shows activation of apoptosis, oxidative stress, and inflammatory pathways and no significant perturbation in controls. Controls show pathway activation of insulin signaling and glucose metabolism, calcium signaling, and energy stress signaling processes compared to no activation in KD muscle. These results indicate that chronic mitochondrial redox stress shifts acute signaling responses away from metabolic signaling pathways and toward oxidative stress and apoptotic signaling processes which may lead to pathological or maladaptive signaling responses over time.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.10.001
JAMA Netw Open. 2026 Oct 01. 9(10): e2638047

Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity: A Randomized Clinical Trial.

Ana Clara da Costa Pinaffi-Langley, Rafal Gulej, Zalan Kaposzta, Zsofia Szarvas, Ali Shahriari, Henry Kinnard, Bryan Ticer, Camila B Pinto, Peter Mukli, Mihaly Muranyi, Cheryl Adams, Jeng Kong, Leah Anderson, Stefano Tarantini, Yan Daniel Zhao, Norman G Hord, Andriy Yabluchanskiy.

Importance: Midlife obesity affects nearly half of US adults and is a major risk factor for chronic diseases. Mitochondrial dysfunction contributes to obesity-related endothelial dysfunction and disease risk, highlighting the mitochondria as a potential intervention target. Urolithin A (UA), a polyphenol-derived microbial metabolite and mitophagy activator, is safe and benefits mitochondrial health in humans.
Objective: To investigate whether supplementation with UA improved peripheral endothelial and cerebrovascular function in middle-aged adults with obesity.
Design, Setting, and Participants: This was a double-blind, placebo-controlled randomized clinical trial conducted at a single site (University of Oklahoma Health Campus) from October 2023 to May 2025. Middle-aged adults (40-64 years) with a body mass index of 30 or greater were eligible to enroll.
Intervention: Enrolled participants were randomized 1:1 to receive 1000 mg of UA or placebo for 4 weeks.
Main Outcomes and Measures: The primary outcome was change in brachial artery flow-mediated dilation (FMD) from baseline to end point comparing control and active groups. Secondary outcomes included complementary peripheral endothelial function measures (reactive hyperemia-induced perfusion fold change and acute reperfusion in the dorsal hand and reactive hyperemia index in the fingertips) and cerebrovascular function measures (task-evoked cerebrovascular hemodynamic responses and task performance). Primary analyses followed the intention-to-treat principle.
Results: Overall, 50 participants were included (25 active and 25 control); mean (SD) age was 50.7 (7.1) years, mean (SD) BMI was 38.3 (7.0), and 37 (74%) were female. Mean (SD) follow-up duration was 28 (2) days. Seven participants were lost to follow-up (14% dropout rate). Change in mean (SD) FMD did not differ significantly based on group allocation (control: 0.3% [5.1%]; active: 1.3% [7.6%]). Similarly, there was no significant treatment effect on secondary peripheral endothelial function outcomes. T-contrast maps showed significantly greater task-evoked hemodynamic responses after supplementation with UA relative to placebo (control: mean [SD] β coefficient, -1.43 [5.26]; active: mean [SD] β coefficient, 15.53 [13.02]), while task performance remained unchanged.
Conclusions and Relevance: In this randomized clinical trial of 50 participants, 4 weeks of UA supplementation did not significantly improve peripheral endothelial function in middle-aged adults with obesity. However, supplementation was well tolerated and feasible, and its effect on task-evoked cerebrovascular hemodynamic responses warrants further investigation.
Trial Registration: ClinicalTrials.gov: NCT05921266.

DOI: https://doi.org/10.1001/jamanetworkopen.2026.38047
Geroscience. 2026 Oct 09.

Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.

Salvatore Nesci, Cristina Algieri.

  Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial dysfunction as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, two central features of biological ageing. We discuss how impaired oxidative phosphorylation, loss of mitochondrial membrane potential, increased electron leak, and excessive reactive oxygen species progressively damage mitochondrial DNA, proteins, and lipids, thereby amplifying organelle dysfunction and compromising cellular homeostasis. Particular emphasis is placed on the threshold effect of mitochondrial DNA mutations, whose age-dependent clonal expansion can drive respiratory chain deficiency in vulnerable tissues. We further analyze mitochondria as signalling platforms that integrate regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and as sources of mitochondrial damage-associated molecular patterns promoting sterile inflammation. Finally, we highlight mitochondrial dysfunction-associated senescence as a central process through which persistent mitochondrial stress reshapes the senescence-associated secretory phenotype and reinforces inflammaging. Overall, the evidence supports a model in which dysfunctional mitochondria act as both initiators and amplifiers of senescence and inflammation, contributing to tissue degeneration and age-related functional decline. Understanding these interconnected mechanisms may help identify therapeutic strategies targeting mitochondrial bioenergetics, inflammatory signalling, and senescent cell burden in ageing.

Keywords:  Ageing; Cell death; DAMPs; Inflammation; Mitochondria

DOI:  https://doi.org/10.1007/s11357-026-02588-y