bims-mistre 2026-03-01 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–03–01
thirty papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
Translational studies of chronic supplementation with a mitochondria-targeted antioxidant to improve physical function with ageing.
Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease.
Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.
Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.
Kynurenine pathway dysregulation in major depressive disorder: the convergence of excitotoxicity, neuroinflammation, and oxidative stress.
Hormonal Modulation with Withania somnifera: Systematic Review and Meta-Analysis of Randomized-controlled Trials.
Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.
Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
Harnessing estrogen's neuroprotective potential in mitigating Alzheimer's pathologies in postmenopausal women: a review.
Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.
Strategic targeting of mitochondria in ischemic heart disease: mechanisms and emerging therapies.
Brain Ketone Bodies in Health, Evolution and Disease.
Next-Generation Antioxidants in Cardiovascular Disease: Mechanistic Insights and Emerging Therapeutic Strategies.
Inositol and Berberine Synergistically Reprogram Endocrine and Ovarian Metabolism in Polycystic Ovary Syndrome.
Modulation of mitochondrial biogenesis by flavonoids via SIRT1 signalling in metabolic syndrome: a systematic review.
Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
Effect of breathing exercises on depression, sexual function, and exercise capacity in postmenopausal women: a randomized controlled trial.
Mitochondrial dysfunction and cellular senescence in ageing sarcopenia with current insights and targeted strategies.
The Gut-Extracellular Vesicle-Mitochondria Axis in Reproductive Aging: Antioxidant and Anti-Senescence Mechanisms.
Oxidative Stress Biomarkers as Predictors of Aging and Age-Related Diseases.
The role of lipids in mediating the effects of immune cells on Alzheimer's disease risk: A network Mendelian randomization study.
The Cut-Off for Triglyceride-Glucose-Body Mass Index (TyG-BMI) and Triglyceride-Glucose-Waist Circumference Index (TyG-WC) Discriminating the Insulin Resistance Based on the SHBG Level and HOMA-IR Value in Caucasian Women with Polycystic Ovary Syndrome.
Mitochondrial oxidative stress to PANoptosis: Current evidence and therapeutic implications for neurological diseases.
Menstrual and reproductive factors and risk of Alzheimer's disease in elderly women: a cohort study in Eastern China.
Rethinking Human Energy Metabolism.
Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics.
Maqui as a Chilean Functional Food: Antioxidant Bioactivity, Nutritional Value, and Health Applications.
Oral magnesium supplementation improves glycemic control in older Chinese adults with pre-diabetes and hypomagnesemia: a randomized controlled trial.
Lemon balm-derived nanovesicles restore mitochondrial functions and reduce cytokine production in skin fibroblasts under pro-inflammatory conditions.

Cells. 2026 Feb 20. pii: 372. [Epub ahead of print]15(4):

Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.

Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton, Michela Casella.

  Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control-encompassing fusion-fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis-compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS-STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.

Keywords:  cardiovascular disease; inflammation; mitochondrial dysfunction; mitochondrial quality control; mitochondrial signaling; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/cells15040372
J Physiol. 2026 Feb 24.

Translational studies of chronic supplementation with a mitochondria-targeted antioxidant to improve physical function with ageing.

Kevin O Murray, Rachel A Gioscia-Ryan, Jaime N Justice, Jessica R Santos-Parker, Nina Z Bispham, David A Hutton, Sanna Darvish, Jill Miyamoto-Ditmon, Zachary S Clayton, Michel Chonchol, Douglas R Seals, Matthew J Rossman.

  Declines in physical function with advancing age increase the risk of functional limitations and chronic disease. Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. Here, we determined the efficacy of the mitochondria-targeted antioxidant MitoQ for improving multiple domains of physical function, first in old mice and then in high-functioning older adults in a randomized, placebo-controlled, cross-over design clinical trial. In old male C57BL6/N mice (N = 22-26; 27 months), we found that 4 weeks of treatment with MitoQ (250 µm in the drinking water) attenuated the age-related decline in grip strength, co-ordination, and endurance without effects in young mice (N = 18-20; 6 months). The effects of MitoQ in old mice were accompanied by lower levels of skeletal muscle mitochondria-specific superoxide production and markers of mitoROS-related oxidative stress (i.e. phosphorylated SHC adaptor protein 1, isoform p66) and inflammation (i.e. interleukin-6, tumour necrosis factor-alpha, interferon-gamma). In the clinical trial, we did not observe convincing effects of 6 weeks of MitoQ (20 mg day-1) treatment on physical function in healthy older adults (N = 18; aged 60-79 years). However, exploratory subgroup analyses suggest possible effects of MitoQ on peak leg extension power and grip strength in participants ≥70 years of age. Our findings provide preclinical, proof-of-concept evidence for targeting excess mitoROS with MitoQ to reverse physical dysfunction with ageing. Although the effects of MitoQ did not directly translate to high functioning older adults, our initial observations suggest MitoQ may have greater efficacy in older, more physically frail individuals. KEY POINTS: Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. In old mice, chronic supplementation with the mitochondria-targeted antioxidant MitoQ improves measures of physical function, which was accompanied by reductions in mitochondria-specific superoxide production in skeletal muscle. The effects of MitoQ in old mice did not directly translate to humans as there were no convincing effects on measures of motor function in a randomized, placebo-controlled, cross-over design clinical trial of 6 weeks of 20 mg day-1 MitoQ. However, in participants ≥70 years of age, we observed possible evidence of efficacy of MitoQ supplementation for improving select measures of strength. Future clinical trials with MitoQ and possibly other mitochondria-targeted antioxidant approaches for enhancing physical function with ageing should focus on older adults of more advanced age or more frail clinical populations.

Keywords:  MitoQ; inflammation; motor function; older adults; postmenopausal women; reactive oxygen species; skeletal muscle; superoxide

DOI:  https://doi.org/10.1113/JP289428
Alzheimers Dement (N Y). 2026 Jan-Mar;12(1):12(1): e70228

Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease.

Matthew K Taylor, Aaron N Smith, In-Young Choi, Phil Lee, Emma Kelly, Tanu Arora, Debra K Sullivan, Jeffrey M Burns, Russell H Swerdlow, Heather M Wilkins.

   BACKGROUND: Creatine monohydrate (CrM) may mitigate bioenergetic failure in Alzheimer's disease (AD) by supporting ATP buffering and modulating mitochondrial function. Building upon our previous findings that CrM is associated with increased brain creatine (Cr) and improved cognition in AD, we investigated our hypothesis that CrM is associated with improved bioenergetic biomarkers in AD.
METHODS: In this single-arm pilot featuring participants with AD (n = 20, 35% female), we investigated changes in bioenergetic biomarkers after 8 weeks of CrM supplementation (20 g/day). We measured brain concentration of N-acetylaspartate (NAA) and glutathione (GSH) using 1H magnetic resonance spectroscopy. We measured platelet and lymphocyte mitochondrial respiration using Oroboros Oxygraph-2K respirometry, lymphocyte adenosine diphosphate (ADP) and adenosine triphosphate (ATP) using a bioluminescent assay, and lymphocyte reactive oxygen species (ROS) with flow cytometry using Amplex Red and MitoSOX. We also investigated sex-dependent bioenergetic responses.
RESULTS: Brain NAA and GSH did not change. In females only, both platelet and lymphocyte mitochondrial respiration increased (p < 0.05; trends for others) across multiple respiration states (State 2, State 3, State 3S, Leak, and Maximum oxygen consumption rate). Lymphocyte ADP (p < 0.02) and ATP (p < 0.001) levels rose significantly in both sexes while ATP/ADP ratio, superoxide, and hydrogen peroxide remained stable.
DISCUSSION: These data suggest CrM may augment systemic energy availability in both sexes and mitochondrial capacity in a sex-specific manner in AD. Interpretation of results from this pilot study is limited by lacking a control group, small sample size, and its relatively short timeframe. However, these preliminary findings support further investigation of CrM as a potential bioenergetic intervention in AD with well-designed RCTs, including exploration of potential sex-specific bioenergetic responses to CrM.
Trial Registration: ClinicalTrials.gov, NCT05383833, registered on May 20, 2022.

Keywords:  Alzheimer's disease; bioenergetics; creatine monohydrate; magnetic resonance spectroscopy; pilot trial

DOI:  https://doi.org/10.1002/trc2.70228
Res Sq. 2026 Feb 12. pii: rs.3.rs-8752767. [Epub ahead of print]

Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.

Kaitlin Casaletto, Madeline Wood Alexander, Jennifer Rabin, Michelle Canuca, Allesandra Iadipaolo, Louisa Cornelis, Nina Miolane, Albert Pham, Julia Borger, Valentina Diaz, Emily Paolillo, Joel Kramer, Laura Pritschet, Caitlin Taylor, Matthew Panizzon, Ramiro Rea Reyes, Marisa Denkinger, Nicholas Ashton, Sterling Johnson, Emily Jacobs, Rowan Saloner.

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (N>3,000) to identify biological changes underlying menopause and its links to brain aging. In N=80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer's disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N=94; N=100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics (N=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and hormone signaling processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

DOI: https://doi.org/10.21203/rs.3.rs-8752767/v1
Int Immunopharmacol. 2026 Feb 20. pii: S1567-5769(26)00249-3. [Epub ahead of print]175 116405

Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.

Qing-Hui Li, Min Ji, Shi-Qi Weng, Xia Li, Qin Xiao, Yan Zhou, Tao Luo, Zhao-Xia Liu.

  Imatinib (IMA), a first-line tyrosine kinase inhibitor for hematologic neoplasms, has been demonstrated to potentially contribute to ovarian dysfunction and potential fertility impairment in premenopausal women following extended therapeutic regimens. As a bioactive flavonoid, quercetin (QUE) possesses diverse therapeutic effects, such as reducing oxidative stress, suppressing inflammation, and delaying aging. In our previous study, we demonstrated that QUE may mitigate IMA-induced ovarian damage, although the specific mechanism remained unclear. In this study, we employed an integrated approach combining network pharmacology with in vivo and in vitro experiments to demonstrate whether IMA induces excessive oxidative stress and mitophagy in ovarian granulosa cells, and further determine whether QUE exerts its protective effects through this pathway. We observed that IMA elevated levels of intracellular reactive oxygen species and mitochondrial superoxide, reduced mitochondrial membrane potential, and enhanced apoptosis in KGN cells. In addition, IMA induced the expression of mitophagy (Pink1 and Parkin) and autophagy (ATG5, P62, and LC3B) flow-related proteins in mice ovaries and KGN cells. Finally, we discovered that IMA activated the expression of p-JNK and c-JUN in both mice ovaries and KGN cells, while inhibited the phosphorylation of mTOR. QUE, reactive oxygen species inhibitor (N-Acetylcysteine) and JNK inhibitor (SP600125) played a restorative role to some extent. Our study establishes a theoretical foundation for the application of natural products in fertility preservation therapy for cancer patients.

Keywords:  Imatinib; Mitophagy; Oxidative stress; Premature ovarian insufficiency; Quercetin; ROS/JNK/c-JUN signaling pathway

DOI:  https://doi.org/10.1016/j.intimp.2026.116405
J Neuroinflammation. 2026 Feb 26.

Kynurenine pathway dysregulation in major depressive disorder: the convergence of excitotoxicity, neuroinflammation, and oxidative stress.

Grace O'Regan, Zoe Plummer, Brian R Christie, Sandy R Shultz, Josh Allen.

  Major depressive disorder (MDD) has traditionally been linked to deficient serotonergic neurotransmission, chronic stress, and heightened inflammation. Compelling evidence implicates the kynurenine pathway (KP), activated by inflammatory cytokines and stress-related signals, as a critical mediator connecting these factors. The KP degrades tryptophan, the metabolic precursor of serotonin, into neuroactive metabolites called kynurenines, such as quinolinic acid and kynurenic acid. Patients with MDD exhibit KP dysregulation, often marked by an overproduction of quinolinic acid, an N-Methyl-D-aspartic acid receptor (NMDAR) agonist that drives excitotoxicity, alongside reduced production of kynurenic acid, an NMDAR antagonist that protects from excitotoxicity and has anti-inflammatory effects. This review examines dysregulation of the KP in MDD, emphasizing KP metabolites - particularly quinolinic acid and kynurenic acid - as biomarkers and mediators of excitotoxicity, neuroinflammation, and oxidative stress, and discusses the therapeutic efficacy of antidepressants that modulate this pathway. Understanding KP dysregulation could inform the development of targeted interventions that address the underlying biological drivers of MDD, offering new hope for patients who do not respond to conventional treatments.

Keywords:  Apoptosis; Astrocytes; Biomarker; Microglia; NMDA receptor; Stress

DOI:  https://doi.org/10.1186/s12974-026-03717-2
Planta Med. 2026 Feb 25.

Hormonal Modulation with Withania somnifera: Systematic Review and Meta-Analysis of Randomized-controlled Trials.

Michal Fornalik, Anna Malkiewicz, Dominika Adamczak, Filip Nawrocki, Aleksandra Zielinska, Samim Ali Mondal.

Hormonal imbalances, particularly involving the hypothalamic-pituitary-adrenal and gonadal axes, contribute to chronic conditions such as stress-related disorders, infertility, and metabolic dysregulation. Ashwagandha (Withania somnifera L.) has been proposed as a potential oral modulator of endocrine function due to its adaptogenic properties. This review aims to systematically evaluate the effects of oral ashwagandha supplementation on circulating hormone levels in adults. Our literature search included MEDLINE, Embase, and ClinicalTrials.gov. The protocol was registered in PROSPERO (CRD42024611576). We included randomized, placebo-controlled trials in adults assessing oral ashwagandha versus placebo that reported changes in hormone levels. Two reviewers independently screened studies, extracted summary data, and assessed risk of bias using the Cochrane tool. Meta-analyses were conducted using a random-effects model to calculate mean differences (MD) or standardized mean differences (SMD), with heterogeneity and publication bias assessed using I² and Egger's test, respectively. Twenty-three trials were included, encompassing 1706 patients. Ashwagandha significantly reduced cortisol (SMD =- 1.18, p < 0.04) and increased serotonin (MD = 31.75 ng/ml, p < 0.01). Subgroup analyses suggested possible dose-response effects based on withanolide content. No effect was found on TSH or T3, but T4 levels increased modestly (MD = 0.61 µg/dL, p = 0.02). Ashwagandha increased testosterone in men (MD = 57.43 ng/dl) but not in women (MD = 5.09 ng/dl), with a significant gender difference. This treatment did not influence E2 levels in either gender. Ashwagandha supplementation appears to modulate key hormonal pathways, particularly cortisol and sex hormones. However, heterogeneity and limited data on some endpoints warrant further standardized trials.

DOI: https://doi.org/10.1055/a-2802-8363
medRxiv. 2026 Feb 11. pii: 2026.02.09.26345907. [Epub ahead of print]

Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer's disease risk.

Madeline Wood Alexander, Jennifer S Rabin, Michelle Caunca, Allesandra Iadipaolo, Louisa Cornelis, Nina Miolane, Albert Pham, Julia Borger, Valentina Diaz, Emily W Paolillo, Joel Kramer, Laura Pritschet, Caitlin Taylor, Matthew S Panizzon, Ramiro Eduardo Rea Reyes, Marisa N Denkinger, Nicholas J Ashton, Sterling C Johnson, Emily G Jacobs, Rowan Saloner, Kaitlin B Casaletto.

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts ( N >3,000) to identify biological changes underlying menopause and its links to brain aging. In N =80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer's disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women ( N =94; N =100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics ( N =2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.

DOI: https://doi.org/10.64898/2026.02.09.26345907
Ageing Res Rev. 2026 Feb 21. pii: S1568-1637(26)00054-1. [Epub ahead of print]117 103062

Linking mitochondrial DNA release to neurodegeneration and cognitive decline.

Zongwei Fang, Catarina Barbosa, Daniela Marinho, Rita Peixoto, Ildete Luísa Ferreira, João Laranjinha, A Cristina Rego.

  Mitochondrial DNA (mtDNA) has been recognized as a key link between mitochondrial dysfunction and neuroinflammation in neurodegenerative diseases. Beyond being a vulnerable target of oxidative damage, mtDNA can act as a damage-associated molecular pattern when released from mitochondria, triggering innate immune signaling pathways in the nervous system. This review synthesizes current evidence on the mechanisms regulating mtDNA escape from mitochondria into the cytosol and its subsequent intracellular and extracellular effects, reframing mtDNA as an active driver of inflammatory processes rather than a passive by-product of mitochondrial injury. We discuss how defects in mitochondrial quality control, particularly impaired mitophagy and macroautophagy, promote the accumulation of damaged mtDNA, including its release via mitochondria-derived vesicles, exosomes or as cell-free mtDNA. By integrating mitochondrial dysfunction, immune activation, and clearance pathways, this review highlights the mitochondria-immune axis as a central contributor to neurodegeneration and cognitive decline, identifying upstream molecular targets with potential for therapeutic intervention.

Keywords:  Damage-associated molecular patterns (DAMPs); Inflammation; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Neurodegenerative diseases; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.arr.2026.103062
Brain Res. 2026 Feb 21. pii: S0006-8993(26)00084-3. [Epub ahead of print]1879 150226

Harnessing estrogen's neuroprotective potential in mitigating Alzheimer's pathologies in postmenopausal women: a review.

Makkapati Manasa, Ganavi Bethanagere Ramesha, K L Krishna, M S Ambika, Abhishek P R Nadig, Suman Pathak, Poornima Jalawadi.

  Alzheimer's disease (AD) is a progressive disorder that affects the brain and leads to cognitive decline and memory loss, with postmenopausal women being unduly affected. Estrogen is believed to exert neuroprotective effects by influencing amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, synaptic function, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. This review examines the role of estrogen in AD pathogenesis among postmenopausal women. A systematic literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included "estrogen", "Alzheimer's disease", "neuroprotection", "amyloid-beta," and "BDNF." Inclusion criteria were peer-reviewed studies from the past 10 years focusing on estrogen's effects on AD mechanisms, neurobiology, and therapeutic relevance. Articles were screened by title and abstract. Followed by a full-text review to ensure methodological rigour and relevance. Evidence indicates that estrogen reduces amyloid beta burden, inhibits tau phosphorylation, mitigates oxidative stress, preserves synaptic connectivity, and suppresses neuroinflammation. Estrogen also modulates ApoE-linked lipid metabolism and enhances BDNF signalling, supporting neuronal survival and cognitive resilience. Declining estrogen after menopause increases vulnerability to AD. Understanding estrogen's neuroprotective mechanisms may support targeted therapeutic strategies. Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs) show potential, but further research is needed to optimise timing, dosage, and patient selection in postmenopausal AD prevention and management.

Keywords:  APOE4; Amyloid beta; BDNF; Estrogen; Synaptic dysfunction; Tau

DOI:  https://doi.org/10.1016/j.brainres.2026.150226
Eur J Med Chem. 2026 Feb 20. pii: S0223-5234(26)00151-0. [Epub ahead of print]308 118706

Dual-action mitochondria-targeted prodrugs that both deplete mitochondrial glutathione and deliver a toxic payload to the matrix.

Patrick A Cardwell, Alva M Casey, Suvagata Roy Chowdhury, Eloïse Marques, Chak Shun Yu, Rebecca L Taig, Stuart T Caldwell, Julien Prudent, Michael P Murphy, Richard C Hartley.

  Mitochondrial glutathione (mGSH) protects the organelle and the cell against reactive oxygen species (ROS), electrophilic metabolites and xenobiotics. Many cancers upregulate GSH to confer resistance against cell death by ferroptosis and anticancer drugs, so mGSH depletion is a potential anticancer strategy. We previously developed MitoCDNB, a mitochondria-targeted molecule that selectively depletes mGSH and disrupts mitochondrial thiol redox homeostasis. However, mGSH depletion by MitoCDNB required catalysis by glutathione-S-transferases (GSTs). Here, we develop a dual-action prodrug scaffold to deplete mGSH independently of GSTs and simultaneously release a payload to increase oxidative stress. The scaffold has four components: a triphenylphosphonium (TPP) group for targeting to the mitochondria, a GSH-reactive electrophilic dinitroaryl ring bearing a sulfonamide leaving group for depleting mGSH, an ethylenediamine-derived self-immolative linker and a phenolic payload. The rates of nucleophilic aromatic substitution (SNAr) of the sulfonamide by GSH and the cyclisation of the released linker-payload intermediate were measured and the kinetics successfully modelled as consecutive reactions. Under physiological levels of GSH (10 mM) and matrix pH (8.0), our best linker releases a 7-hydroxycoumarin reporter with a half-life of 2.5 min at 30 °C. We used the scaffold for cellular and mitochondrial uptake of a compound that depletes mGSH and releases the redox-cycling pro-oxidant, menadiol/menadione, in the mitochondrial matrix. The combination of mGSH depletion with enhanced mitochondrial ROS production showed synergistic cytotoxicity towards cancer cells, paving the way for the development of dual-action mitochondria-targeted prodrugs as potential cancer therapeutics.

Keywords:  Cancer; Glutathione; Mitochondria; Oxidative stress; Prodrug; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.ejmech.2026.118706
Expert Rev Cardiovasc Ther. 2026 Feb 24.

Strategic targeting of mitochondria in ischemic heart disease: mechanisms and emerging therapies.

Gino A Kurian, Eren Rose Gino.

   INTRODUCTION: Ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Mitochondrial dysfunction is central to ischemia - reperfusion injury, contributing to bioenergetic failure, oxidative stress, calcium overload, and impaired adaptive responses, making mitochondria an important therapeutic target.
AREAS COVERED: This review integrates mechanistic and translational evidence linking mitochondrial dysfunction, structural injury, and adaptive-response failure in IHD. Key pathways discussed include reverse electron transport - driven reactive oxygen species generation, mitochondrial permeability transition pore activation, disrupted fusion - fission dynamics, mitophagy imbalance, and proteostasis collapse. Emerging therapeutic strategies such as mitochondria-targeted antioxidants, cardiolipin-stabilizing peptides, metabolic modulators, mitochondrial transplantation, and genome-directed approaches are evaluated alongside diagnostic innovations including circulating mitochondrial DNA, mitomiRs, and molecular imaging. A structured literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published between January 2000 and March 2025.
EXPERT OPINION: Precision targeting of mitochondrial injury and adaptive failure offers stage-specific therapeutic opportunities in IHD; however, successful translation requires biomarker-guided stratification, optimized delivery systems, and temporally aligned clinical trial design.

Keywords:  Ischemic heart disease; cardiolipin; ischemia–reperfusion injury; mitochondrial biomarkers; mitochondrial dysfunction; mitochondrial permeability transition pore; mitochondrial quality control; precision cardiology

DOI:  https://doi.org/10.1080/14779072.2026.2637751
Cells. 2026 Feb 23. pii: 382. [Epub ahead of print]15(4):

Brain Ketone Bodies in Health, Evolution and Disease.

Pierre Bougnères.

  Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to ~2 mM. As a fuel, KBs provide the brain with acetyl-CoA that produces ATP or glutamate, notably in certain brain regions. Remarkably, KBs activate the expression of their own cerebral transporters and KB-utilizing enzymes so that circulating levels determine cerebral utilization of KBs. Throughout evolution, the energetic role of KBs has been crucial for the metabolic homeostasis of humans endowed with a large brain and facing unpredictable periods of food shortage. Paradoxically, the brain of modern, regularly fed humans whose ordinary blood KBs are ~0.1 mM, has access to much fewer circulating sources of energy than that of their distant ancestors. KBs can modify certain proteins post-translationally, for example, histones through lysine-butyrylation. KBs could act as short- or long-term epigenetic messengers. These properties of KBs might allow a fetus to directly sense maternal starvation and adapt their cerebral metabolism to this situation, possibly preparing for nutritional constraints in extra-uterine life. KB transcriptional and epigenetic properties could also enable the postnatal organism to retain a molecular memory of its own starvation episodes. No other energy substrate, such as glucose or lactate, has such capacities. Medicine turned its attention to KBs a century ago. Indeed, KBs are the only energy substrates whose circulating levels can be increased, and nutritional interventions can alter them under free-living conditions. This property opens broad prospects for ketogenic diets (KDs) to prevent or rescue neurodegenerative diseases characterized by glucose hypometabolism, notably Alzheimer's disease (AD). However, KDs have not yet found real medical applications, for reasons that are discussed.

Keywords:  Alzheimer; brain; evolution; ketogenic diet; ketone bodies

DOI:  https://doi.org/10.3390/cells15040382
Antioxidants (Basel). 2026 Jan 25. pii: 164. [Epub ahead of print]15(2):

Next-Generation Antioxidants in Cardiovascular Disease: Mechanistic Insights and Emerging Therapeutic Strategies.

Desh Deepak Singh, Dharmendra Kumar Yadav, Dongyun Shin.

  Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. CVDs are associated with multiple factors, including oxidative stress, mediated endothelial dysfunction, vascular inflammation, and atherothrombosis. Although traditional antioxidant supplementation (such as vitamins C, E, and β-carotene) has shown promising results in rigorous animal model studies, it has consistently failed to demonstrate clinical benefit in most human trials. Consequently, there is a substantial unmet need for novel paradigms involving mechanistically and biologically relevant pharmaceutical-grade antioxidant therapies ("next-generation antioxidants"). Rapid advancements in redox biology, nanotechnology, genetic modulation of redox processes, and metabolic regulation have enabled the development of new antioxidant therapeutics, including mitochondrial-targeted agents, NADPH oxidase (NOX) inhibitors, selenoprotein and Nrf2 activators, engineered nanoparticles, catalytic antioxidants, and RNA-based and gene-editing strategies. These interventions have the potential to modulate specific oxidative pathways that contribute to CVD pathogenesis. This review provides a comprehensive assessment of current oxidative stress-modulating modalities and their potential to inform personalized cardiovascular prevention and treatment strategies.

Keywords:  NADPH oxidase (NOX) inhibitors; Nrf2 activation; cardiovascular disease prevention; mitochondria-targeted antioxidants; nanotechnology-based antioxidant delivery; oxidative stress

DOI:  https://doi.org/10.3390/antiox15020164
Cell Prolif. 2026 Feb 27. e70188

Inositol and Berberine Synergistically Reprogram Endocrine and Ovarian Metabolism in Polycystic Ovary Syndrome.

Juan Ge, Chenxiang Zhang, Yilong Zhao, Haiyang Zhao, Shuai Zhu, Tao Tang, Guorui Zhang, Qiang Wang, Hui Wang.

  Although Myo-Inositol/D-Chiro-Inositol (Ins) and berberine (BBR) have each shown beneficial effects in polycystic ovary syndrome (PCOS), their combined therapeutic potential has not been systematically evaluated. Here, we demonstrate that Ins/BBR exerts superior efficacy compared with single treatments by targeting multiple pathogenic pathways in PCOS. In a DHEA+HFD-induced mouse model, Ins/BBR restored systemic sex steroid balance, normalized LH/FSH ratio, and improved estrous cyclicity. It also reduced ovarian cysts and enhanced fertility, accompanied by partial normalization of steroidogenic enzyme expression. At the cellular level, Ins/BBR alleviated mitochondrial defects and broadly reprogrammed metabolic landscape in granulosa cells, in specific, restoring nucleotide pools and amino acid turnover and preventing abnormal long-chain fatty acid accumulation. Together, these findings provide preclinical evidence that Ins/BBR acts through coordinated endocrine, ovarian and metabolic mechanisms, supporting its promise as a safe and effective therapeutic strategy for PCOS.

Keywords:  berberine; granulosa cell; inositol; polycystic ovary syndrome; reproduction

DOI:  https://doi.org/10.1111/cpr.70188
Mol Biol Rep. 2026 Feb 24. pii: 422. [Epub ahead of print]53(1):

Modulation of mitochondrial biogenesis by flavonoids via SIRT1 signalling in metabolic syndrome: a systematic review.

Prastuti Sahariah, Lunasmrita Saikia, Albert Bharali, Douglas Law, Saikat Sen, Partha Pratim Dutta.



Keywords:  Dyslipidaemia; Flavanols; Insulin Resistance; Mitochondrial Dysfunction; SIRT1

DOI:  https://doi.org/10.1007/s11033-026-11599-z
Biomolecules. 2026 Feb 14. pii: 302. [Epub ahead of print]16(2):

Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.

Fanny Fontaine, Romain Pénicaud, Stéphane Allouche.

  Coenzyme Q10 (CoQ10) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ10 participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ10 deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ10 biosynthesis. These defects lead to reduced CoQ10 levels and impaired mitochondrial functions. Clinically, primary CoQ10 deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ10, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ10 biology, biosynthesis, and the clinical spectrum of primary CoQ10 deficiencies, and we discuss emerging mechanisms linking CoQ10 depletion to mitochondrial dysfunctions and human diseases.

Keywords:  coenzyme Q10; metabolism; mitochondrial disorders; mitophagy; oxidative phosphorylation; oxidative stress; primary coenzyme Q10 deficiency

DOI:  https://doi.org/10.3390/biom16020302
Sci Rep. 2026 Feb 23.

Effect of breathing exercises on depression, sexual function, and exercise capacity in postmenopausal women: a randomized controlled trial.

Saher Lotfy Elgayar.



Keywords:  Breathing exercises; Depression; Menopause; Sexual function; Women

DOI:  https://doi.org/10.1038/s41598-026-41198-8
Mol Biol Rep. 2026 Feb 27. pii: 444. [Epub ahead of print]53(1):

Mitochondrial dysfunction and cellular senescence in ageing sarcopenia with current insights and targeted strategies.

Veepin Dwivedi, Rushikesh Thanekar, Kanchan Khare, Brijesh Taksande, Milind Umekar, Shubhada Mangrulkar.



Keywords:  Cellular Senescence; Mitochondrial Dysfunction; Oxidative Stress; Sarcopenia

DOI:  https://doi.org/10.1007/s11033-026-11609-0
Antioxidants (Basel). 2026 Jan 28. pii: 174. [Epub ahead of print]15(2):

The Gut-Extracellular Vesicle-Mitochondria Axis in Reproductive Aging: Antioxidant and Anti-Senescence Mechanisms.

Efthalia Moustakli, Christina Messini, Anastasios Potiris, Athanasios Zikopoulos, Ioannis Arkoulis, Alexios Kozonis, Theodoros Karampitsakos, Pavlos Machairoudias, Nikolaos Machairiotis, Panagiotis Antsaklis, Periklis Panagopoulos, Sofoklis Stavros, Ekaterini Domali.

  Cellular senescence, mitochondrial dysfunction, and cumulative oxidative stress (OS) are the main causes of the progressive decreases in oocyte and sperm quality that define reproductive age. There is growing evidence that these processes are controlled by systemic variables, such as metabolites produced from the gut microbiome and extracellular vesicle (EV)-mediated intercellular communication, rather than being exclusively regulated at the tissue level. Antioxidant enzymes, regulatory microRNAs, and bioactive lipids that regulate mitochondrial redox balance, mitophagy, and inflammatory signaling are transported by EVs derived from reproductive organs, stem cells, immune cells, and the gut microbiota. Concurrently, microbiome-derived metabolites such as urolithin A, short-chain fatty acids, and polyphenol derivatives enhance mitochondrial quality control, activate antioxidant pathways, and suppress senescence-associated secretory phenotypes. This narrative review integrates the most recent research on the relationship between redox homeostasis, mitochondrial function, gut microbiota activity, and EV signaling in the context of male and female reproductive aging. We propose an emerging gut-EV-mitochondria axis as a unified framework through which systemic metabolic and antioxidant signals affect gamete competence, reproductive tissue function, and fertility longevity. Finally, we discuss therapeutic implications, including microbiome modulation, EV-based interventions, and senotherapeutic strategies, highlighting key knowledge gaps and future research directions necessary for clinical translation.

Keywords:  antioxidants; cellular senescence; extracellular vesicles; fertility; gut microbiome; mitochondrial function; mitophagy; oxidative stress; reproductive aging; reproductive longevity

DOI:  https://doi.org/10.3390/antiox15020174
J Gerontol A Biol Sci Med Sci. 2026 Feb 23. pii: glag056. [Epub ahead of print]

Oxidative Stress Biomarkers as Predictors of Aging and Age-Related Diseases.

Yogesh Kumar, Anuja Pant, Somu Yadav, Pawan Kumar Maurya.

  Oxidative Stress (OS) is a major feature of aging and is first brought on when the generation of Reactive Oxygen Species (ROS) surpasses the capacity of antioxidant defenses to neutralize them. Long-term exposure to ROS gradually damages vital biomolecules, resulting in the development of measurable biomarkers that indicate the degree of oxidative stress. Some forms of protein oxidation that impair enzymatic activity and interfere with cellular signaling are carbonyl compounds and advanced oxidation protein products. DNA is susceptible to OS, which can cause lesions like 8-hydroxy-2-deoxyguanosine, which indicate genomic instability and lead to cellular senescence and reduced function. Increased levels of lipid peroxidation byproducts, such as Malondialdehyde (MDA), 4-hydroxynonenal (4-NHE), and isoprostanes, indicate disturbed cellular balance and compromised membrane integrity. Additional information about the redox state can be found in antioxidant defenses. While important enzymatic antioxidants like glutathione peroxidase, catalase, and superoxide dismutase frequently show altered activity as one ages, indicating a reduced ability to counteract ROS, non-enzymatic antioxidants like glutathione, vitamins C and E, uric acid, bilirubin, and beta carotene provide extra defense but diminish with age. Combined, these biomarkers show how oxidative damage accumulates gradually and how the body's cellular defenses progressively deteriorate. By mapping their trajectories, we can better understand the biology of aging and develop targeted interventions and early detection tools to promote healthy aging. In this review, we summarized various OS biomarkers that help in the prediction of aging and age-related diseases.

Keywords:  Antioxidants; Biomarkers; Oxidative Stress; ROS; Superoxide dismutase

DOI:  https://doi.org/10.1093/gerona/glag056
J Prev Alzheimers Dis. 2026 Feb 20. pii: S2274-5807(26)00033-6. [Epub ahead of print]13(4): 100509

The role of lipids in mediating the effects of immune cells on Alzheimer's disease risk: A network Mendelian randomization study.

Xinyu Yang, Jingjing Jiang, Wenjing Li, Rui Pan, Yanjie Li.

   BACKGROUND: Observational studies have shown associations between immune cells, lipids, and Alzheimer's disease (AD), but their specific causal relationships and the mediating role of lipids remain unclear.
METHODS: Within a network Mendelian randomization (MR) framework, we first applied two-sample univariable MR to assess the causal effects of immune cells and lipids on AD. Then, multivariable MR was used in mediation analyses to determine whether lipids mediate the effects of immune cells on AD. Finally, reverse MR analyses were performed to minimize potential bias from reverse causation. The inverse variance weighted method was used as the primary estimator.
RESULTS: The analysis revealed that elevated levels of CD33 on CD33dim HLA DR+ CD11b+ and CD33 on CD33dim HLA DR+ CD11b- were associated with an increased risk of AD. Mediation analysis further indicated that polyunsaturated fatty acids are protective lipid metabolites for AD and partially mediate the effects of the aforementioned immune cells on AD, with mediation proportions of 3.70 % and 3.67 %, respectively.
CONCLUSION: This study provides new insights into how immune cells may influence AD pathogenesis through lipid metabolism. It also offers a theoretical basis and potential direction for developing immune-lipid-based strategies for AD prevention and intervention.

Keywords:  Alzheimer's disease; Immune cells; Lipids; Mediation analysis; Mendelian randomization

DOI:  https://doi.org/10.1016/j.tjpad.2026.100509
Medicina (Kaunas). 2026 Feb 01. pii: 291. [Epub ahead of print]62(2):

The Cut-Off for Triglyceride-Glucose-Body Mass Index (TyG-BMI) and Triglyceride-Glucose-Waist Circumference Index (TyG-WC) Discriminating the Insulin Resistance Based on the SHBG Level and HOMA-IR Value in Caucasian Women with Polycystic Ovary Syndrome.

Tahar Ben Rhaiem, Aleksander Jerzy Owczarek, Mariusz Wójtowicz, Dariusz Ciura, Paweł Madej, Magdalena Olszanecka-Glinianowicz, Jerzy Tadeusz Chudek.

  Background and Objectives: Cut-off points for the triglyceride-glucose-body mass index (TyG-BMI) and the triglyceride-glucose-waist circumference index (TyG-WC) have been established for the assessment of insulin resistance (IR) only in the population of Asian women with polycystic ovary syndrome (PCOS). Therefore, the present study aimed to estimate the cut-off value for these indices discriminating the IR based on the homeostatic model assessment for insulin resistance (HOMA-IR) and sex hormone binding globulin (SHBG) levels established previously in Caucasian women with PCOS. Material and Methods: The medical records of 264 selected young adults (18-40 y.o.) Caucasian women with PCOS were the source of parameters: age, body weight, height, waist circumference, glucose, insulin, triglyceride, and SHBG levels, used for calculation of TyG-BMI and TyG-WC indices. The cut-off values for TyG-BMI and TyG-WC indices were calculated using receiver operating characteristic curve analysis. Results: The study group included 68 overweight (25.8%) and 62 overweight (23.4%) women. The empirical optimal cut-off values for TyG-BMI and TyG-WC indices corresponding to HOMA-IR values ≥ 2.1 were 233 and 735 [area under the curve (AUC) 85.1% and 86.7%, accuracy 0.814 and 0.784, sensitivity 66.3% and 67.3%, specificity 90.4% and 84.9%, PPV 80.2% and 72.5%, NPV 82.0% and 81.5%], respectively. The empirical optimal cut-off values for TyG-BMI and TyG-WC indices corresponding to SHBG levels < 41.5 nmol/L were 230 and 734 (AUC 79.5% and 77.1%, accuracy 0.735 and 0.723, Se 57.4% and 57.4%, Sp 87.3% and 85.2%, PPV 79.5% and 76.9%, NPV 70.4% and 69.9%), respectively. Conclusions: The cut-offs for the TyG-BMI and TyG-WC indices discriminating IR in young Caucasian women with PCOS were similar regardless of whether they are based on HOMA-IR values or SHBG levels.

Keywords:  PCOS; TyG-BMI index; TyG-WC index; glucose; insulin resistance; lipids

DOI:  https://doi.org/10.3390/medicina62020291
J Adv Res. 2026 Feb 19. pii: S2090-1232(26)00156-6. [Epub ahead of print]

Mitochondrial oxidative stress to PANoptosis: Current evidence and therapeutic implications for neurological diseases.

Ye He, Limin Guo, Lewen Wang, Zixin Li, Rui Lu, Xinxing Wan, Na Liu, Weitao Yan, Haifeng Wang, Qi Zhang, Kun Xiong.

   BACKGROUND: Mitochondrial oxidative stress is a key driver of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and spinal cord injury, promoting neuronal dysfunction and degeneration through multiple pathways. PANoptosis, a recently characterized regulated cell death pathway integrating pyroptotic, apoptotic, and necroptotic signaling, exacerbates neuroinflammation and accelerates neuron loss. Emerging evidence reveals the important role of mitochondrial oxidative stress in inducing PANoptosis through complex mechanisms associated with reactive oxygen species overproduction, mitochondrial DNA damage, and impaired mitochondrial dynamics.
AIM OF REVIEW: This review aims to summarize current knowledge on the mechanisms and roles of PANoptosis in neurological diseases, with a focus on its interplay with mitochondrial oxidative stress.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review provides insight into the intricate crosstalk between mitochondrial oxidative stress and the activation of PANoptosis, particularly through caspase activation, necroptotic signaling, and pyroptotic pathways. Furthermore, we highlight emerging therapeutic interventions that target these mechanisms. These strategies have shown promise in attenuating neuroinflammation and neuronal death, offering hope for the development of targeted therapies to address the complex pathophysiology of neurological diseases.

Keywords:  Mitochondrial dysfunction; Necroptosis; Oxidative stress; PANoptosis; Pyroptosis

DOI:  https://doi.org/10.1016/j.jare.2026.02.023
Sci Rep. 2026 Feb 24.

Menstrual and reproductive factors and risk of Alzheimer's disease in elderly women: a cohort study in Eastern China.

Fudong Li, Kun Chen, Tao Zhang, Le Xu, Xue Gu, Junfen Lin, Jianmin Jiang.

  Epidemiological studies suggest that proxies of lifetime estrogen exposure are associated with the risk of Alzheimer's disease (AD). However, results remain limited and inconsistent. This study aimed to examine whether menstrual and reproductive factors, proxies of estrogen exposure, are associated with the risk of AD in Chinese postmenopausal women. Information on menstrual and reproductive factors was obtained through the baseline survey of the Zhejiang Ageing and Health Cohort Study. During the three follow-up waves, AD diagnoses were conducted. We excluded participants with prevalent cognitive impairment or incomplete data of cognitive assessment at baseline, and incident cases of cognitive impairment without AD diagnosis across follow-up. Log-binomial model and the generalized additive model (GAM), controlled for a wide range of potential confounders, were generated to examine the association. Finally, 5606 women were included, and 597 developed AD during follow-up. The age of participants ranged from 60 to 95 years (mean = 65.7 years, SD = 6.5) at baseline. Women with a longer reproductive lifespan (> 34 years, compared with 32-34 years) had a lower risk of AD (RR = 0.81, 95% CI 0.67-0.98). Menopause due to ovariectomy was associated with a higher risk of AD (RR = 2.17, 95% CI 1.16-4.08), compared to those with natural menopause. The shorter length of menstrual cycles (≤ 27 days, compared with 28-30 days) was associated with an increased risk of AD (RR = 1.47, 95% 1.15-1.87), and shorter length of menstrual period (≤ 3 days, compared with 4-6 days) was associated with a decreased risk of AD (RR = 0.73, 95% 0.59-0.90). Women with 2 or more parity showed a higher risk of AD, while women with 2 or more miscarriages and abortions had a lower risk of AD. Older age at first childbirth (> 22 years, compared with 21-22 years) was associated with a decreased risk of AD (RR = 0.47, 95% CI 0.38-0.58). A U-shaped association was identified between mean breastfeeding duration and AD. Oral contraceptive use was also associated with an increased risk of AD. Our results show that menstrual and reproductive factors are statistically significantly associated with the risk of AD in Chinese postmenopausal women.

Keywords:  Alzheimer’s disease; Cohort study; Menstrual history; Reproductive history

DOI:  https://doi.org/10.1038/s41598-026-40329-5
Curr Issues Mol Biol. 2026 Feb 01. pii: 159. [Epub ahead of print]48(2):

Rethinking Human Energy Metabolism.

Alexander Panov, Vladimir Mayorov, Sergey Dikalov, Alexandra Krasilnikova, Lev Yaguzhinsky.

  For a long time, glycolysis and mitochondrial oxidative phosphorylation were opposed to each other. Glycolysis works when there is a lack of oxygen; the mitochondria supply ATP in an oxygen environment. In recent decades, it has been discovered that glycolysis in vivo always works and the final product is lactate. Lactate can accumulate and is the transport form for pyruvate. In this review, we look at how obligate lactate formation during glycolysis affects the tricarboxylic acid (TCA) cycle and mitochondrial respiration. We conclude that fatty acid β-oxidation is a prerequisite for obligate lactate formation during glycolysis, which in turn promotes and enhances the anaplerotic functions of the TCA cycle. In this way, a supply of two types of substrates for mitochondria is formed: fatty acids as the basic energy substrates, and lactate as an emergency substrate for the heart, skeletal muscles, and brain. High steady-state levels of lactate and ATP, supported by β-oxidation, stimulate gluconeogenesis and thus support the lactate cycle. It is concluded that mitochondrial fatty acids β-oxidation and glycolysis constitute a single interdependent system of energy metabolism of the human body.

Keywords:  beta-oxidation of fatty acids; energy metabolism; fatty acids; glycolysis; lactate; lactate cycle; mitochondria; pyruvate; respirasome; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/cimb48020159
Biomedicines. 2026 Jan 30. pii: 316. [Epub ahead of print]14(2):

Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics.

Noelia Garzon-Escamilla, Miriam Medina-Cardena, Preeti Roy, Jessica Trent, Joud Jamous, Yalini Somesan, Sandy J Denslow.

  Aging is a multifactorial biological process marked by the progressive decline in cellular and physiological functions, increasing susceptibility to chronic diseases and mortality. Recent research has identified the gut microbiome as a key modulator of aging, influencing immune regulation, metabolic homeostasis, and neuroendocrine signaling. A diverse and balanced gut microbiota promotes healthspan by supporting gut barrier integrity, nutrient metabolism, and anti-inflammatory responses, whereas dysbiosis contributes to the onset and progression of age-related diseases, including neurodegeneration, cardiovascular conditions, cancer, and metabolic disorders. Currently, anti-aging interventions targeting key aging pathways, such as insulin/IGF-1 signaling, mTOR, AMPK, and sirtuins, are a major focus in the field of geroscience. Compounds such as metformin, rapamycin, anti-inflammatories, GLP-1 agonists, senolytics, spermidine, SGLT2 inhibitors, and sirtuin activators have shown lifespan extension in animal models. In humans, some of these interventions are associated with improvements in healthspan-related outcomes, including metabolic, cardiovascular, musculoskeletal, respiratory, cognitive and ocular functions. Notably, the gut microbiome may serve as both a mediator and modulator of these interventions, influencing drug metabolism, efficacy, and host responses. This review synthesizes current evidence on the gut microbiome's role in aging, examining its role as both mediator and modulator of longevity interventions and how microbiome-associated mechanisms intersect with emerging anti-aging therapeutics.

Keywords:  GLP-1; SGLT2i; aging; anti-inflammatories; gut microbiome; metformin; rapamycin; senolytics; sirtuins; spermidine

DOI:  https://doi.org/10.3390/biomedicines14020316
Antioxidants (Basel). 2026 Feb 03. pii: 204. [Epub ahead of print]15(2):

Maqui as a Chilean Functional Food: Antioxidant Bioactivity, Nutritional Value, and Health Applications.

Caterina Tiscornia, Enrique Lorca, Carolina Estremadoyro, Valeria Aicardi, Fabián Vásquez.

  Maqui (Aristotelia chilensis) is a berry native to southern Chile, recognized for its high content of phenolic compounds, particularly delphinidin-type anthocyanins, which confer strong antioxidant and anti-inflammatory properties and have generated growing interest as a functional food. Its scientific relevance has increased due to advances in understanding its biological mechanisms, including the Nrf2 signaling pathway, modulation of systemic inflammation, improvement in mitochondrial function, and potential applications in cardiometabolic, renal, and vascular health. Objective: The objective of this study is to analyze the available evidence on maqui in relation to its nutritional composition, bioactive profile, antioxidant and anti-inflammatory mechanisms, bioavailability, and emerging clinical applications in the prevention and/or treatment of chronic non-communicable diseases. Main findings: Maqui is rich in delphinidins, dietary fiber, and antioxidant micronutrients and modulates key oxidative stress and inflammatory pathways, including Nrf2-HO-1 and NF-κB. Preclinical and early clinical evidence supports its cardiometabolic and nephroprotective effects, with improvements in glycemic control, lipid metabolism, oxidative stress, and endothelial function. Conclusions: Maqui shows considerable potential as a Chilean functional food with antioxidant and anti-inflammatory effects relevant to human health. However, robust clinical trials and formulations with enhanced bioavailability are required to consolidate its therapeutic application.

Keywords:  Aristotelia chilensis; anthocyanins; antioxidants; delphinidins; inflammation; oxidative stress

DOI:  https://doi.org/10.3390/antiox15020204
Front Nutr. 2026 ;13 1765308

Oral magnesium supplementation improves glycemic control in older Chinese adults with pre-diabetes and hypomagnesemia: a randomized controlled trial.

Jingxin Yang, Huidi Zhang, Yuting Li, Wenxuan Wu, Min Pan, Jingjing Wang, Guoxun Li, Ying Wu, Chunlei Guo, Lichen Yang, Jing Ding, Gangqiang Ding.

   Purpose: Pre-diabetes significantly increases the risk of type 2 diabetes and cardiovascular disease. Magnesium deficiency is common and may contribute to dysglycemia. However, evidence for the efficacy of magnesium supplementation in pre-diabetes, especially in older adults with hypomagnesemia, remains limited and inconclusive. This exploratory trial aimed to evaluate the effects of oral magnesium supplementation on glycemic parameters and conducted exploratory metabolomic profiling in this population.
Methods: In this 4-month, randomized, double-blind, placebo-controlled trial, 71 community-dwelling older adults (mean age 68.7 ± 6.0 years) with pre-diabetes (fasting plasma glucose ≥5.6 mmol/L and/or HbA1c 5.7%-6.5%) and hypomagnesemia (plasma magnesium ≤ 0.80 mmol/L) were enrolled. Participants were randomly assigned to receive either magnesium oxide (360 mg elemental Mg/day) or an identical placebo once daily. The primary outcome was the change in fasting plasma glucose (FPG). Secondary outcomes included changes in insulin, HOMA-IR, HbA1c, glycated albumin, and inflammatory markers (hs-CRP, IL-6). Exploratory non-targeted metabolomic profiling was performed. Data were analyzed using ANCOVA adjusted for baseline values, following the intention-to-treat principle.
Results: Sixty-five participants completed the trial. At baseline, the magnesium group had significantly higher insulin and HOMA-IR levels (both p < 0.05); analyses were adjusted accordingly. Compared to placebo, magnesium supplementation significantly increased plasma magnesium (adjusted mean difference: 0.056 mmol/L, 95% CI: 0.028 to 0.085; p < 0.001) and reduced FPG (adjusted mean difference: -0.497 mmol/L, 95% CI: -0.818 to -0.176; p = 0.003). The reduction in HOMA-IR favored the magnesium group but was not statistically significant after adjustment (p = 0.296). No significant between-group differences were observed for HbA1c, insulin, C-peptide, glycated albumin, or inflammatory markers. Exploratory metabolomics revealed alterations in putatively identified metabolites, with pathway analysis suggesting involvement of lipid and insulin resistance-related pathways; these findings are considered hypothesis-generating.
Conclusion: In older adults with pre-diabetes and hypomagnesemia, magnesium supplementation effectively corrected magnesium deficiency and reduced FPG, but did not improve other glycemic indices including HbA1c or insulin resistance. The clinical significance of the isolated FPG reduction remains uncertain. The metabolomic findings require validation. Larger, longer-term trials are needed to determine if magnesium supplementation can prevent diabetes in this population.
Clinical trial registration: www.chictr.org.cn, identifier: ChiCTR2100047666.

Keywords:  RCT; magnesium deficiency; magnesium supplement; older Chinese adults; pre-diabetes

DOI:  https://doi.org/10.3389/fnut.2026.1765308
Eur J Pharm Sci. 2026 Feb 23. pii: S0928-0987(26)00057-6. [Epub ahead of print] 107483

Lemon balm-derived nanovesicles restore mitochondrial functions and reduce cytokine production in skin fibroblasts under pro-inflammatory conditions.

Gabrielė Kulkovienė, Martyna Uldukytė, Sofiya Haluts, Emilija Mikalauskienė, Monika Iešmantaitė, Giedrė Tamulaitienė, Giedrius Sasnauskas, Ramunė Morkūnienė, Aistė Jekabsone.

  Mitochondrial dysfunction, particularly excessive fission, has been implicated in inflammatory signalling in skin diseases such as psoriasis and atopic dermatitis (AD). Current systemic treatments, while effective, are often associated with adverse effects, variable patient responses and high costs. Plant extracts have shown notable anti-inflammatory properties; however, their therapeutic potential is limited due to low penetration and poor bioavailability. Thus, plant-derived nanovesicles (PDNVs) have emerged as an alternative delivery platform, offering bioactive cargo with improved skin penetration and low immunogenic potential. Melissa officinalis L. (Lemon Balm, LB) extracts have demonstrated beneficial effects in inflammatory skin conditions; however, the potential of LB-NVs to modulate skin cell function and cellular energetics in inflammatory conditions remains unexplored. Thus, this study investigated the effects of LB-NVs on mitochondrial function and structure in human skin fibroblasts exposed to a cytokine cocktail (IL-22, IL-17A, TNF-α) to induce a pro-inflammatory state (PInfS). LB-NVs rescued cells from inflammatory metabolic reprogramming by restoring mitochondrial respiration and preventing elevated glycolysis induced by PinfS. Additionally, they reduced mitochondrial fragmentation by regulating the activation of Drp1 and lowered the total p38 MAPK level. Lastly, LB-NVs suppressed IL-4 and IL-13, which are central to AD pathogenesis, and reduced IL-18, a cytokine that commonly increases with disease activity. These findings, for the first time, demonstrate the ability of PDNVs to directly target mitochondrial functions and modulate inflammation, positioning LB-NVs as a highly promising strategy for treating chronic skin inflammation.

Keywords:  Plant-derived nanovesicles; atopic dermatitis; inflammation; lemon balm; mitochondria; psoriasis

DOI:  https://doi.org/10.1016/j.ejps.2026.107483