bims-mistre 2026-04-19 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–04–19
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.
Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes.
Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.
Fluoxetine reprograms hippocampal mitochondrial subcellular proteomes in chronically socially isolated rats.
GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.
Growth Differentiation Factor 15 and Physical Function Impairment in the SardiNIA Study.
Mitochondrial medicine in obesity: a scoping review.
Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Burden and Mortality in a Population-Based Cohort.
STOML2 Alleviates Osteoarthritis by Regulating Mitochondrial Energy Metabolism and Oxidative Stress.
Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.
MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.
Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities.
Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.
Optimizing Brain Biology Through Near-Infrared-Induced Mitochondrial Melatonin Synthesis: A Hypothesis Paper.
Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.
Diet, the Gut Microbiome, and Estrogen Physiology: A Review in Menopausal Health and Interventions.
Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity.
The duality of estrogen.
The role of mitochondrial dysfunction, oxidative stress, and gender in cardiac fibrosis and vascular remodeling in an induced aged rat model with possible mitigation by eugenol nano-emulsion.
Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
The complex relationship between oxidative stress and aging: new perspectives on similarities and differences.
18-β-glycyrrhetinic acid facilitates nuclear-mitochondrial communications to alleviate oxidative stress through HMGB1-cGAS-Mul1 axis in tendinopathy.
Modulation of Glucose Homeostasis, Metabolic Endotoxemia and Circulating Short-Chain Fatty Acids Following Multi-Species Probiotic Supplementation: Findings from a 12-Week Randomised Placebo-Controlled Trial.
DNMT3A drives mitochondrial dysfunction in intracerebral hemorrhage via PGC-1α promoter hypermethylation.

Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 17.

Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.

Adelene Gan-Yin-Xuen, Soni Thakur, Mohd Adnan, Sreenivasan Sasidharan.

  Mitochondrial biogenesis, the process by which cells generate new mitochondria, is crucial for maintaining cellular homeostasis, energy production, and overall health. Mitochondrial dysfunction is a key factor in both aging and cancer, where it contributes to the decline in cellular function and facilitates the progression of disease. In aging, mitochondrial alterations lead to impaired metabolic function, increased oxidative stress, and cellular senescence. Similarly, cancer cells often exhibit altered mitochondrial dynamics, which support rapid proliferation and resistance to apoptosis. Despite their differences, aging and cancer share common molecular mechanisms, particularly in mitochondrial dysregulation, that offer insights into potential therapeutic strategies. Recent research has highlighted the potential of medicinal plants and their bioactive compounds in modulating mitochondrial biogenesis and mitigating dysfunction. Phytochemicals have shown promise in enhancing mitochondrial function, promoting healthy aging, and inhibiting cancer progression. This review explores the molecular mechanisms underlying mitochondrial biogenesis, its dysregulation in aging and cancer, and the therapeutic potential of plant-based compounds in targeting mitochondrial dysfunction. By understanding the intricate relationship between mitochondria, aging, and cancer, novel therapeutic strategies can be developed to improve cellular health and combat age-related diseases and cancer.

Keywords:  Aging; Cancer; Mitochondrial biogenesis; Mitochondrial dysfunction; Phytochemicals

DOI:  https://doi.org/10.1007/s00210-026-05299-5
bioRxiv. 2026 Apr 07. pii: 2026.04.05.716515. [Epub ahead of print]

Sulfide:quinone oxidoreductase drives mitochondrial supersulfide metabolism to regulate bioenergetics and longevity in eukaryotes.

Jia Yao, Tetsuro Matsunaga, Akira Nishimura, Meg Shieh, Tomoaki Ida, Minkyung Jung, Seiryo Ogata, Tsuyoshi Takata, Uladzimir Barayeu, Hozumi Motohashi, Masanobu Morita, Takaaki Akaike.

Sulfide:quinone oxidoreductase (SQR) is a critical enzyme that maintains sulfur metabolism by oxidizing sulfide to supersulfides, currently defined as sulfur metabolites with six valence electrons and no charge that are covalently catenated with other sulfur atoms and excludes disulfides. While SQR is known to contribute to mitochondrial electron transport, its physiological impact on systemic energy metabolism and longevity remains largely undefined. In this study, we investigated the role of SQR in mitochondrial bioenergetics and aging using SQR-deficient Schizosaccharomyces pombe ( Δhmt2 ) and a mitochondria-selective SQR-deficient ( Sqrdl ΔN/ΔN ) mice model. Functional analysis demonstrated that Δhmt2 grew normally in glucose but not in glycerol, indicating impaired mitochondrial respiration. It showed reduced membrane potential, ATP, and lifespan. Consistent with the yeast findings, Sqrdl ΔN/ΔN mice exhibited accumulated levels of hydrogen sulfide and persulfides, and demonstrated impaired mitochondrial energy metabolism. Furthermore, supersulfide donor supplementation selectively conferred lifespan extension in wild-type yeast, but not in SQR-deficient strain, and similarly improved mitochondrial function exclusively in wild-type mouse embryonic fibroblasts, with no benefit observed in SQR-mutant counterparts. Together, our findings demonstrate that mitochondrial SQR plays an essential role in sulfur respiration, critically supporting mitochondrial function and organismal longevity across eukaryotes.
Graphic Abstract:
Highlights: Developed an SQR-deficient S. pombe ( Δhmt2 ) model that exhibits sulfur metabolism, mitochondrial dysfunction, and shortened chronological lifespan Sulfide and supersulfide donors prolong yeast lifespan in a SQR-dependent mannerMitochondrial SQR is essential for membrane potential formation and ATP production in yeast and mammals.

DOI: https://doi.org/10.64898/2026.04.05.716515
Aging Dis. 2026 Apr 13.

Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.

Suman Rimal, Jae-Hyuk Lee, Yanzi He, Bingwei Lu.

Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer's disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.

DOI: https://doi.org/10.14336/AD.2026.0011
Rev Neurosci. 2026 Apr 16.

Fluoxetine reprograms hippocampal mitochondrial subcellular proteomes in chronically socially isolated rats.

Snežana B Pajović, Dragana Filipović.

  Brain mitochondrial dysfunction may play a crucial role in the mechanisms of major depressive disorders, impairing neuronal bioenergetics and synaptic transmission. While the antidepressant fluoxetine (Flx) is primarily known for modulating serotonin levels, it may also enhance mitochondrial function in stress-affected brain regions, particularly the hippocampus. This review summarizes findings from proteomic analyses of hippocampal nonsynaptic mitochondria (NSM) and synaptosomal mitochondria from adult male rats subjected to six weeks of chronic social isolation (CSIS), an animal model of depression, followed by Flx treatment lasting three weeks of six-week CSIS, compared to CSIS. In NSM of CSIS rats, Flx upregulates proteins involved in pyruvate metabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and ATP synthesis, suggesting an overall enhancement of mitochondrial energy production. Additional upregulation encompasses one-carbon folate metabolism, mitochondrial transport, structural organization, and proteostasis. Within synaptosomal mitochondria, Flx induces a distinct yet complementary proteomic signature, upregulating selects TCA cycle enzymes and catalytic OXPHOS components, remodeling the respiratory chain to support enhanced bioenergetic capacity. Flx further upregulates proteins mediating ketone body and amino acid catabolism, antioxidant defense system and protein quality control mechanisms. Notably, monoamine oxidase-A exhibits consistent upregulation across both mitochondrial subpopulations, likely representing a compensatory response to maintain monoamine homeostasis. These findings suggest that Flx mediates part of its antidepressant effects through subcellular compartment-specific reprogramming of the mitochondrial proteome, underscoring mitochondria as one of the modulators of depression-related molecular alterations and potential therapeutic targets.

Keywords:  depression; energy metabolism; fluoxetine; mitochondria; proteomics

DOI:  https://doi.org/10.1515/revneuro-2025-0152
J Mol Med (Berl). 2026 Apr 14. pii: 64. [Epub ahead of print]104(1):

GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.

Ayushi Sood, Joshua Peterson, Jayashree Jena, Vamsi Challa, Caden Washburn, Randy J Seeley, Renata O Pereira.

  Growth differentiation factor 15 (GDF15) is a cytokine induced in several tissues in response to stress. GDF15 suppresses food intake and increases energy expenditure via its actions on the glial-derived neurotrophic factor receptor α family-like specific receptor (GFRAL), located in the hindbrain. We recently showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes (OPA1 BKO) leads to GDF15 secretion, partially mediating resistance to diet-induced obesity (DIO), and improving thermoregulation. To investigate whether GDF15 signaling through GFRAL is necessary to mediate these metabolic effects, we crossed OPA1 BKO mice with GFRAL global knockout mice (DKO). Under isocaloric conditions, DKO mice had similar body weight as control and OPA1 BKO mice. Upon high-fat diet feeding, DKO mice were partially resistant to DIO, but lacked the improvement in glucose homeostasis and insulin sensitivity observed in OPA1 BKO mice. Finally, DKO mice were susceptible to cold-induced hypothermia, suggesting a role for GFRAL in core body temperature regulation in the OPA1 BKO mice. Our data reveals a novel BAT-GDF15-GFRAL axis that modulates resistance to DIO and improves thermoregulation in mice in the context of mitochondrial stress. KEY MESSAGES: OPA1 deletion induces a BAT-GDF15-GFRAL axis to regulate systemic metabolic homeostasis. GDF15-signaling through GFRAL partially mediates resistance to DIO in mice lacking OPA1 in BAT. GFRAL mediates GDF15's effects on energy homeostasis in DIO OPA1 BKO mice. GDF15-GFRAL signaling is required to maintain core body temperature in cold-exposed OPA1 BKO mice.

Keywords:  Brown adipose tissue; GDF15; GFRAL; OPA1; Obesity; Thermoregulation

DOI:  https://doi.org/10.1007/s00109-026-02671-z
J Clin Med. 2026 Mar 29. pii: 2612. [Epub ahead of print]15(7):

Growth Differentiation Factor 15 and Physical Function Impairment in the SardiNIA Study.

Nicia I Profili, Edoardo Fiorillo, Valeria Orrù, Maria Benelli, Francesco Cucca, Alessandro P Delitala.

  Background: Sarcopenia is the age-related, progressive loss of strength, function, and skeletal muscle mass, which can be assessed with specific tests. The Growth differentiation factor 15 (GDF-15) has been proposed as a key biomarker of aging, and it has been associated with mitochondrial dysfunction, cachexia, and physical impairment. Methods: The cohort of this study comes from the SardiNIA study, an ongoing longitudinal survey focused on the identification of genetic and phenotypic variants associated with aging. We assessed hand grip strength, gait speed, and GDF-15 in all samples. Linear multivariate analysis was used to assess the correlation after adjusting for a range of potential confounders. Results: The sample consisted of 4842 subjects (57.5% female) with a median age of 48.6 years. Levels of GDF-15 were comparable between males and females and showed a strong positive association with aging (rho 0.617, p < 0.001). Linear multivariate regression analyses showed that GDF-15 was negatively associated with gait speed and grip strength in both hands (respectively, Beta -0.09, Beta -0.07, and Beta -0.08, p < 0.001 for all). Conclusions: GDF-15 was negatively associated with physical function. GDF-15 may be considered a proxy for reduced physical performance. Future research is needed to understand the pathogenetic role of GDF-15 in the reduction in skeletal muscle in aging people.

Keywords:  GDF-15; gait speed; grip strength; mitochondrial dysfunction; reduced physical performance; skeletal muscle

DOI:  https://doi.org/10.3390/jcm15072612
Open Med (Wars). 2026 Jan;21(1): 20261407

Mitochondrial medicine in obesity: a scoping review.

Amedeo Lonardo, Ralf Weiskirchen.

   Introduction: Mitochondrial dysfunction connects obesity and metabolic dysfunction. We conducted a scoping review on mitochondria in obesity to (i) describe morpho-functional mitochondrial abnormalities across tissues and (ii) summarize mitochondria-directed lifestyle and pharmacological strategies and their metabolic effects.
Content: PubMed and Web of Science were searched, using relevant keywords. English-language original studies, clinical trials, and systematic reviews were qualitatively synthesized in a scoping review conducted in accordance with the PRISMA extension for Scoping Reviews and prospectively registered in the Open Science Framework.
Summary: Sixty primary articles and cross-references describe nutrient overload-induced oxidative stress, disturbed mitochondrial dynamics and mitophagy, and maladaptive endoplasmic reticulum (ER)-mitochondria contacts across various organ tissues and cancer. These changes are associated with insulin resistance, steatotic liver disease, chronic kidney disease, cardiovascular dysfunction, impaired fertility, and tumor progression. Reported interventions include mitochondria-targeted antioxidants, AMPK/SIRT1/PGC-1α activators, modulators of ER-mitochondria coupling, microbiota-directed approaches, and lifestyle changes. Common mitochondrial signatures, excess reactive species, impaired quality control, and altered organelle crosstalk, underlie systemic metabolic derangement, supporting mitochondria as a unifying therapeutic target.
Outlook: Obesity involves widespread mitochondrial changes in various organs. Approaches that improve mitochondrial health through lifestyle and medication may help manage obesity complications and need thorough clinical testing.

Keywords:   muscle; adipose tissue; female fertility; kidneys; pancreas; steatotic liver disease

DOI:  https://doi.org/10.1515/med-2026-1407
Int J Mol Sci. 2026 Mar 27. pii: 3078. [Epub ahead of print]27(7):

Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Burden and Mortality in a Population-Based Cohort.

Beatriz Martín-Carro, Leticia Nieto-García, Clara Sánchez-Pablo, Alfonso Romero, Candelas Pérez Del Villar, José Carlos Moyano-Maza, José María de Dios, David Cembrero-Fuciños, Estefanía Iglesias-Colino, Paz Muriel, Sara Cascón, Amalia Martín-Gallego, Baltasara Blázquez, Inmaculada Santolino, Lydia González-González, María Concepción Ledesma, Javier Maillo-Seco, Jesús Rodríguez-Nieto, Luis M Rincón, María Isidoro-García, Pedro L Sánchez.

  Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine strongly associated with aging, multimorbidity, and cardiovascular disease. Although prior studies have established its prognostic value in high-risk populations, its role in the general population remains less defined. The aim of this study was to determine if there is an association between plasma GDF15 levels, heart disease and mortality in a representative population-based cohort. We analyzed 1532 participants (mean age 55 years; 54.6% women) with available baseline plasma GDF15 concentrations. Participants were stratified according to an optimal cutoff of 1081 pg/mL, derived from ROC curve analysis for mortality. Associations with prevalent heart disease were assessed using multivariable logistic regression models adjusted for cardiovascular risk factors and NT-proBNP. Mortality was analyzed using Cox proportional hazards models, with model performance evaluated by C-index and time-dependent ROC curves. Individuals with GDF15 > 1081 pg/mL were older and exhibited a more adverse cardiometabolic profile with higher prevalence of comorbidities. Elevated GDF15 was independently associated with ischemic cardiomyopathy (OR 3.34, 95% CI: 1.38-8.11), particularly in men (OR 4.26, 95% CI: 1.40-12.96), but not in women. No independent associations were observed with arrhythmias, valvulopathy, or heart failure after adjustment for NT-proBNP. During a median follow-up of 6.2 years, 51 deaths occurred. Elevated GDF15 independently predicted all-cause mortality (HR 2.47, 95% CI: 1.19-5.13), though the effect was attenuated after adjustment for NT-proBNP. GDF15 improved model discrimination (ΔC-index = +0.01; LRT p = 0.011) and showed robust time-dependent predictive ability, with AUCs of 0.76, 0.82, and 0.85 at 2, 4, and 6 years, respectively. In this population-based cohort, elevated GDF15 identified individuals with an adverse health profile, was independently associated with ischemic cardiomyopathy in men, and predicted mortality. Although its incremental predictive value over NT-proBNP was modest, GDF15 could provide complementary biological information and may enhance multimarker strategies for cardiovascular risk stratification in the general population.

Keywords:  GDF15; cardiovascular disease; mortality; multimorbidity; population-based cohort

DOI:  https://doi.org/10.3390/ijms27073078
Genet Res (Camb). 2026 ;2026(1): e9303825

STOML2 Alleviates Osteoarthritis by Regulating Mitochondrial Energy Metabolism and Oxidative Stress.

Fei Xie, Kun Miao, Hao Wu, Xuejun Wu.

  Osteoarthritis (OA) is associated with chondrocyte dysfunction and cartilage degeneration, but how mitochondrial homeostasis is maintained during OA progression remains incompletely understood. Here, we show that Stomatin-like protein 2 (STOML2) is downregulated in IL-1β-stimulated chondrocytes and in human OA cartilage. STOML2 depletion impairs oxidative phosphorylation, elevates mitochondrial reactive oxygen species, and promotes chondrocyte senescence and ferroptotic cell death. Mechanistically, STOML2 interacts with the mitochondrial Na+/Ca2+ exchanger (NCLX) to support mitochondrial Ca2+ efflux and metabolic stability. Restoring STOML2 enhances NCLX-dependent Ca2+ handling, mitigates mitochondrial Ca2+ overload and the glycolytic shift, and improves ATP production. In a rat OA model, intra-articular delivery of STOML2 attenuates cartilage degeneration and reduces inflammatory changes in the joint. Together, these findings identify a STOML2-NCLX axis that safeguards mitochondrial Ca2+ homeostasis and chondrocyte viability, suggesting STOML2 as a potential therapeutic target for OA.

Keywords:  STOML2; mitochondrial dysfunction; osteoarthritis; oxidative stress

DOI:  https://doi.org/10.1155/genr/9303825
J Physiol. 2026 Apr 14.

Oleuropein-based olive leaf extract enhances muscle mitochondrial bioenergetics response to moderate - but not maximal - intensity exercise in humans.

Clément Lanfranchi, Alba Moreno-Asso, Astrid M H Horstman, Sara Mistro, Eugenia Migliavacca, Ornella Cominetti, Jens Stolte, Sylviane Métairon, Aurélie Hermant, Ane Laura Pedersen, Loïc Dayon, Umberto De Marchi, Jérôme N Feige, Nadège Zanou, Nicolas Place.

  Sprint interval exercise (SIE) induces skeletal muscle mitochondrial adaptations that are comparable to, or greater than, those observed with moderate-intensity continuous exercise (MICE), despite requiring a lower training volume. Previous work has shown that these adaptations are at least partly mediated by enhanced mitochondrial bioenergetics, including increased mitochondrial Ca2+ uptake and resulting pyruvate dehydrogenase (PDH) activation. In parallel, the natural compound oleuropein from olive leaf extract (OLE) promotes mitochondrial Ca2+ uptake and activates PDH in mouse skeletal muscle. Here, we tested the hypothesis that OLE intake would activate PDH and potentiate mitochondrial adaptations in human skeletal muscle during either MICE or SIE. In a crossover, double-blind study, healthy males performed MICE (1 h at 50% maximal aerobic power, n = 11) or SIE (6 × 30 s all-out sprints with 4 min recovery, n = 10). Knee extensor neuromuscular tests and vastus lateralis muscle biopsies were performed before, immediately after and 24 h after SIE or MICE. OLE improved the decline of power output during the first sprint in SIE and reduced heart rate during MICE but did not affect knee extensor fatigability after both exercise modalities. Transcriptomic analyses revealed an effect of OLE on the mitochondrial and inflammatory response after MICE and SIE, while OLE increased PDH activity in combination with exercise only following MICE. Together, these results suggest that OLE modulates skeletal muscle response to exercise and pave the way for future investigations aiming to investigate the chronic effect of combining OLE and exercise training. KEY POINTS: Previous studies have shown that oleuropein increases mitochondrial calcium uptake in preclinical models and that mitochondrial calcium uptake contributes to skeletal muscle mitochondrial adaptations in response to maximal intensity exercise in humans. Olive leaf extract (OLE) increases the activity of pyruvate dehydrogenase, a proxy of mitochondria calcium uptake, when combined with moderate-intensity exercise. Combining moderate-intensity continuous exercise and sprint interval exercise with OLE enhances the mitochondrial response at a transcriptional level. OLE enhances skeletal muscle mitochondrial response to acute exercise, paving the way for investigating its effect in combination with chronic exercise training protocols.

Keywords:  calcium mitochondria; muscle fatigue; oxidative phosphorylation; power output; pyruvate dehydrogenase

DOI:  https://doi.org/10.1113/JP290316
Aging Dis. 2026 Apr 02.

MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.

Giacoma Galizzi.

Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca2+) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.

DOI: https://doi.org/10.14336/AD.2025.1342
Pharmacol Res. 2026 Apr 15. pii: S1043-6618(26)00110-6. [Epub ahead of print] 108195

Mitochondrial Dysfunction and Immunoinflammatory Remodeling in Heart Failure: Emerging Role of the mtDNA-cGAS/STING Axis and Therapeutic Opportunities.

Xi Zhang, Xiangchen Xia, Yanmin Zhang, Xiaomin Liu, Xiaoyu Wei, Shichuan Chen, Yuchen Song, Yicheng Chen, Jianzhong Pang, Qiang Xu, Fuyun Jia.

  Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with persistent sterile inflammation emerging as a critical driver of maladaptive cardiac remodeling beyond hemodynamic stress alone. Recent advances have repositioned mitochondria from passive bioenergetic organelles to active immunometabolic signaling hubs. In this context, mitochondrial DNA (mtDNA) leakage during mitochondrial dysfunction acts as a potent damage-associated molecular pattern (DAMP), engaging the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and amplifying inflammatory cascades that accelerate cardiomyocyte loss, fibrosis, and ventricular failure. In this review, we integrate current evidence linking mitochondrial quality control failure-including oxidative stress, metabolic reprogramming, impaired mitophagy, and dysregulated mitochondrial dynamics-to aberrant activation of the mtDNA-cGAS/STING axis in HF. We further highlight how this pathway contributes to pro-inflammatory remodeling of the cardiac immune microenvironment, thereby establishing a self-sustaining immunoinflammatory loop that perpetuates disease progression. Importantly, we discuss emerging pharmacological strategies targeting this axis, ranging from mitochondrial-directed antioxidants and mitophagy enhancers to small-molecule cGAS/STING inhibitors and advanced cardiac-targeted delivery platforms. Collectively, the mtDNA-cGAS/STING pathway represents a unifying and druggable immunometabolic framework in HF, offering promising opportunities for precision anti-inflammatory intervention and therapeutic innovation.

Keywords:  Mitochondrial dysfunction; cGAS/STING pathway; heart failure; immune inflammation; mitochondrial DNA leakage; therapeutic strategies

DOI:  https://doi.org/10.1016/j.phrs.2026.108195
Cells. 2026 Mar 28. pii: 603. [Epub ahead of print]15(7):

Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.

Bartosz Osuch, Patrycja Młotkowska, Elżbieta Marciniak, Tomasz Misztal.

  Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases.

Keywords:  AMPK–PGC-1α; BDNF; FNDC5; irisin; mitochondrial homeostasis; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells15070603
Geriatr Gerontol Int. 2026 Apr;26(4): e70484

Association of Mitochondrial DNA Levels in Peripheral Blood Leukocytes With Physical Performance in Older Adults.

Hiroaki Ikezaki, Ryoko Nakashima, Hideyuki Nomura, Nobuyuki Shimono.

   BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) in peripheral blood leukocytes has emerged as a surrogate marker of mitochondrial function. This study examined associations between leukocyte mtDNA-CN, physical performance, and lipid metabolism in community-dwelling older adults.
METHODS: We conducted a cross-sectional analysis of 594 adults aged ≥ 50 years (median 71 years; 351 women, 243 men) who were independent in activities of daily living. Physical performance was assessed using handgrip strength and gait parameters measured with a triaxial accelerometer. Frailty status was evaluated using the Japanese version of the Cardiovascular Health Study (J-CHS) criteria. Blood samples were collected after fasting for mtDNA-CN and other blood chemical measurements.
RESULTS: Median values of mtDNA-CN were 124 in women and 114 in men. According to the J-CHS criteria, 6.1% of women and 6.3% of men were classified as frail, while 48.9% of women and 53.6% of men were pre-frail. Participants with higher mtDNA-CN levels demonstrated superior physical performance. After multivariable adjustment, mtDNA-CN correlated positively with gate ability in women and handgrip strength in men. In addition, mtDNA-CN correlated positively with iron in women and high-density lipoprotein cholesterol (HDL-C) in men, and negatively with uric acid and C-reactive protein in men. In the multivariate regression analyses, mtDNA-CN still showed positive associations with handgrip strength and HDL-C, a negative association with uric acid in men, and a positive association with iron in women and men.
CONCLUSION: Leukocyte mtDNA-CN was associated with physical performance, suggesting its potential utility as a biomarker for frailty assessment in older adults.

Keywords:  frailty; gait speed; handgrip; mitochondrial DNA; triglycerides

DOI:  https://doi.org/10.1111/ggi.70484
Cureus. 2026 Mar;18(3): e105322

Optimizing Brain Biology Through Near-Infrared-Induced Mitochondrial Melatonin Synthesis: A Hypothesis Paper.

Joseph Mercola.

  The human brain consumes approximately 20% of total energy production despite comprising only 2% of body mass, rendering neurons particularly vulnerable to oxidative damage. Modern indoor lifestyles have dramatically reduced exposure to near-infrared (NIR) radiation, a component of sunlight that penetrates biological tissues. Concurrently, age-related declines in both pineal melatonin production and mitochondrial function have been implicated in the pathogenesis of neurodegenerative diseases. Additionally, aging is associated with declining availability of glutathione precursors, particularly glycine and cysteine, which may limit endogenous antioxidant responses even when enzymatic capacity is preserved. This hypothesis paper synthesizes evidence from photobiomodulation (PBM) research, mitochondrial biology, and melatonin biochemistry to propose a mechanistic framework whereby NIR radiation activates mitochondrial melatonin synthesis, potentially triggering an antioxidant cascade that may confer neuroprotection. The framework explicitly incorporates the requirement for adequate glutathione precursor substrate availability as a potential rate-limiting factor. A targeted narrative synthesis informed the development of the proposed mechanistic framework. Peer-reviewed publications were identified through searches of PubMed, Web of Science, and Google Scholar (1990-2025) using terms related to PBM, mitochondrial melatonin, glutathione metabolism, and neuroprotection. Studies were selected based on relevance to the proposed framework, with emphasis on mechanistic studies, randomized controlled trials, and systematic reviews. Priority was given to publications from 2020 to 2025, while seminal foundational studies were retained regardless of publication date. Evidence supporting each component of the proposed cascade was categorized by strength to maintain transparency regarding the distinction between established findings and untested hypotheses. The proposed NIR-mitochondrial melatonin-glutathione cascade represents a biologically plausible mechanism for endogenous neuroprotection, contingent upon adequate substrate availability. While substantial evidence supports individual components, the integrated hypothesis requires rigorous experimental validation. Concurrent attention to glutathione precursor status through glycine and N-acetylcysteine (NAC) supplementation may be necessary to realize the full therapeutic potential of this approach.

Keywords:  alzheimer's disease; cytochrome c oxidase; glutathione; mitochondrial melatonin; near-infrared light; neuroprotection; photobiomodulation

DOI:  https://doi.org/10.7759/cureus.105322
Front Pharmacol. 2026 ;17 1781376

Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.

Siyi Guo, Fei Yu, Chao Wang, Wenbing Zhao, Xuan Li, Jiayi Liu, Zhida Lyu.

  Schisandrin B (Sch B) is a dibenzocyclooctadiene lignan derived from plants of the Schisandra genus. Owing to its pronounced lipophilicity, Sch B may readily cross biological membranes and is increasingly discussed in association with the regulation of mitochondrial homeostasis. Mitochondrial dysfunction underlies key pathological processes involved in multi-organ injury and a broad range of chronic diseases, manifested as redox imbalance, reduced mitochondrial membrane potential (ΔΨm), impaired ATP production, mitochondrial DNA (mtDNA) damage, disrupted mitochondrial dynamics, failure of mitochondrial quality control, and amplified inflammation, thereby promoting cell death and tissue remodeling. Accumulating evidence in recent years suggests that Sch B exerts biological effects associated with improved mitochondrial function in multiple models involving the liver, kidney, heart, brain, lung, and tumors. However, previous reviews have primarily focused on overall pharmacological activities or individual diseases, and a cross-organ integrative framework with "mitochondria" as the central axis remains limited. Based on current evidence, the mitochondria-related actions of Sch B can be summarized at several complementary levels: maintaining redox balance; stabilizing ΔΨm and potentially modulating the threshold of the mitochondrial permeability transition pore (mPTP); improving calcium homeostasis and bioenergetic output; reshaping the balance between fusion and fission; context-dependently regulating autophagy/mitophagy and autophagic flux; and bidirectionally influencing mitochondria-mediated apoptotic pathways in distinct cellular settings. At the organ level, the effects of Sch B exhibit a "pathology-driven matching" pattern: in acute stresses such as ischemia-reperfusion, Sch B tends to enhance mitochondrial stress tolerance and promote energy recovery; in toxin/drug-induced injury, it more prominently delays membrane structural disruption and oxidative damage; whereas in metabolic chronic diseases, its actions are associated with metabolic flexibility and the continuity of quality control processes. Despite the cross-organ consistency of Sch B in mitochondrial regulation, its translation remains constrained by factors including in vivo exposure, effective intramitochondrial concentration, delivery and targeting strategies, safety boundaries, and interindividual variability. Therefore, this review proposes a multi-organ mechanistic model centered on "mitochondrial homeostasis regulation," providing a theoretical basis for understanding the cross-system effects of Sch B and for future drug development and optimization.

Keywords:  mechanism; mitochondrial homeostasis; multi-organ protection; schisandrin B; translational challenges

DOI:  https://doi.org/10.3389/fphar.2026.1781376
Nutrients. 2026 Mar 26. pii: 1052. [Epub ahead of print]18(7):

Diet, the Gut Microbiome, and Estrogen Physiology: A Review in Menopausal Health and Interventions.

Michelle Jing Sin Lim, Elvina Parlindungan, E'ein See, Ching Hwee Gan, Rachel Yap, Germaine Jia Min Yong.

  Menopause represents a key transitional phase in women's health, characterized by declining estrogen levels and increased risk for cardiometabolic, musculoskeletal, and urogenital disorders. Beyond its endocrine roots, emerging evidence highlights the gut microbiome as a critical modulator of systemic hormonal balance. This review synthesizes current understanding of the bidirectional relationship between estrogen and the gut microbiome and its implications for women's health during menopause. Evidence from current studies reveals distinct findings across populations, reflecting the complexity of estrogen regulation in part by the gut microbiome (i.e., estrobolome). While no ideal gut microbial composition has been identified for women across stages of perimenopause, likely due to geographically unique gut microbiome profiles among healthy women, greater microbial diversity has been positively associated with improved estrogen regulation. Conversely, reduced diversity and altered Firmicutes/Bacteroidetes ratios have been linked to biomarkers of inflammation during perimenopause, which is a key driver across many perimenopausal symptoms. Although hormone replacement therapy remains the primary clinical intervention during perimenopause, we highlight emerging evidence on the adjuvant potential of diet, synbiotics, phytoestrogens, and strain-specific probiotics in modulating the estrogen-gut microbiome axis for improved health span trajectories and better symptom management. Future longitudinal studies integrating diet, gut microbiome profiles and symptom trajectories are essential to clarify these mechanisms across ethnicity and geography. Ultimately, understanding localized diet-microbiome interactions will enable the development of accessible, personalized, and non-hormonal strategies to complement and increase agency in proactive management during the perimenopausal transition.

Keywords:  estrobolome; gut microbiome; perimenopause; personalized nutrition; synbiotics

DOI:  https://doi.org/10.3390/nu18071052
Nutr Res Pract. 2026 Apr;20(2): 220-238

Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity.

So Young Kwon, Khuhee Na, Yerim Han, Seungmin Song, Yoon Jung Park.

   BACKGROUND/OBJECTIVES: Supplementation of nicotinamide adenine dinucleotide (NAD) precursors has been investigated for its potential to counteract age-related physiological decline. While decreased NAD+ level is associated with conditions such as obesity and dyslipidemia, few studies have explored its metabolic impact in relatively young animals. Here, we hypothesized that nicotinamide mononucleotide (NMN) could alleviate high-fat diet-induced metabolic stress in young mice and sought to elucidate the underlying mechanisms.
MATERIALS/METHODS: We first conducted a secondary analysis of hepatic transcriptome datasets from multiple NMN intervention studies to identify target pathways. Next, 11-week-old lean and obese C57BL/6N mice administrated NMN (500 mg/kg/day) for 1 mon were analyzed for metabolic parameters and gene expression for the target pathways. In vitro study using AML12 cell line was then conducted to confirm the effects of NMN. Additionally, transcriptomic data from liver-specific nicotinamide phosphoribosyltransferase (NAMPT)-deficient mice were analyzed to examine the relationship between NAD+ metabolism, endoplasmic reticulum (ER) stress, and circadian rhythm.
RESULTS: The secondary analysis of hepatic transcriptome datasets revealed potential target pathways related to circadian regulation and hepatic ER stress. In mouse study, short-term NMN administration significantly decreased body weight and fat mass. NMN also alleviated hepatic ER stress response in vivo and in vitro. Additional analysis revealed that the mice with diet-induced metabolic stress or NAMPT deficiency led to phase shifts of the hepatic circadian core clock oscillation by advancing the peak time, while time-restricted feeding shifted the opposite, indicating the metabolic regulation of the circadian phase.
CONCLUSION: Short-term NMN administration effectively attenuated obese condition in young mice and mitigated hepatic ER stress. The altered ER stress was regulated by NAMPT, potentially through the phase shift of the hepatic circadian rhythm.

Keywords:  Nicotinamide mononucleotide; circadian rhythm; endoplasmic reticulum stress; liver; obesity

DOI:  https://doi.org/10.4162/nrp.2026.20.2.220
Neuron. 2026 Apr 15. pii: S0896-6273(26)00131-5. [Epub ahead of print]114(8): 1329-1331

The duality of estrogen.

Skylar Cassity, Elizabeth Gould.

Estrogen enhances cognition under healthy and pathological conditions. In this issue of Neuron, Hokenson et al.1 describe findings that counter this view, demonstrating that high levels of brain estrogen during acute intense stress impair memory. This preview discusses their findings in context of stress-induced pathology and resilience.

DOI: https://doi.org/10.1016/j.neuron.2026.02.026
Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 13.

The role of mitochondrial dysfunction, oxidative stress, and gender in cardiac fibrosis and vascular remodeling in an induced aged rat model with possible mitigation by eugenol nano-emulsion.

Rawan H Hanafi, Marwa S Khattab, Sara M Baraka, Saber Ibrahim, Samar H Elsharkawy, Reda M S Korany.

  Cardiac diseases are strongly associated with aging and pose a major threat to survival. This study evaluated the cardioprotective effects of oral eugenol and its nano-emulsion (20 mg/kg) in a D-galactose-induced aging model (300 mg/kg, i.p.) in male and female rats over 12 weeks. Particle size and zeta potential analyses confirmed the successful development of a stable, well-dispersed nano-emulsion system. At the end of treatment, echocardiography, biochemical assays, histopathology, and immunohistochemistry were performed. Cardiac dysfunction and dilatation were more pronounced in males than females following D-galactose administration, as evidenced by left ventricular internal diameter in diastole (LVIDd) and left ventricular internal diameter in systole (LVIDs), and reduced ejection fraction (EF) and fractional shortening (FS). Both eugenol and its nano-emulsion preserved cardiac architecture and mitigated histopathological alterations, including myofibrillar distortion, necrosis, vascular remodeling, and fibrosis. Treatment significantly reduced oxidative stress and mitochondrial dysfunction by restoring GSH, lowering MDA, and modulating the PINK1/Mfn2 pathway. Furthermore, eugenol and its nano-emulsion attenuated cardiac inflammation, apoptosis, and fibrosis through downregulation of TGF-β1, MMP-9, TNF-α, and caspase-3 expression. In conclusion, eugenol nano-emulsion demonstrates promising anti-aging potential against cardiac complications by regulating mitochondrial dynamics, mitophagy, oxidative stress, inflammatory and apoptotic responses, and the SIRT1/TGF-β/MMP9 signaling pathway.

Keywords:  Aging; Eugenol; Histopathology; Mitophagy; Nanoemulsion

DOI:  https://doi.org/10.1007/s00210-026-05262-4
bioRxiv. 2026 Apr 07. pii: 2026.04.04.716514. [Epub ahead of print]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.

Hyperphosphorylation and aggregation of the microtubule-associated protein tau are recognized as pathological hallmarks of tauopathies; however, the biological activity of tau that drives its pathophysiological effects remains poorly understood 1-6 . Mitochondrial dysfunction is a common feature of tauopathies 7,8 . Despite this, the mechanistic link between tau abnormalities and mitochondrial dysfunction, as well as its relationship to tau's physiological function, remains unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess ROS, reduces the NAD + /NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cells (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers significant stress resistance. Mechanistically, tau enters mitochondria and directly interacts with the mitochondrial complex I (C-I) subunit NDUFS3, enhancing RET activation in a phosphorylation-dependent manner that correlates with tau pathogenicity. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Blocking tau entry into mitochondria or disrupting tau/NDUFS3 interaction reduces tau-induced RET. Genetic or pharmacological inhibition of RET protects against tau-induced neurodegeneration across species. RET regulation represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for conditions characterized by tau abnormalities and mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2026.04.04.716514
Crit Rev Clin Lab Sci. 2026 Apr 16. 1-33

The complex relationship between oxidative stress and aging: new perspectives on similarities and differences.

Xue-Song Liu, Chenglong Zhu, Haoling Zhang, Wangzheqi Zhang.

  The association of oxidative stress with aging is considered one of the key theoretical cornerstones in aging research, but accumulating evidence has cast some doubt on the validity of a single "cumulative oxidative damage" hypothesis as its mechanism. This review aims to provide a comprehensive and updated overview of the complex interplay between oxidative stress and aging, with a particular focus on their shared mechanisms and context-dependent effects. ROS should not be regarded only as deleterious metabolic waste, but indeed act as pivotal signaling mediators in metabolic, stress, and cell fate regulation within the frame of physiological ranges. In addition, emerging evidence highlights the dual roles of ROS in maintaining cellular homeostasis and mediating stress responses depending on their concentration and spatial distribution. Only when the fine-tuned equilibrium that usually couples ROS production and disposal is perturbed and quality-control activity becomes defective does this signaling network gradually shift from a physiological into a pathological source of stress promoting cellular senescence and tissue malfunction. Aging should thus be considered the outcome of structural derangement in homeostatic regulatory networks caused by chronic stress. This view of the aging process is developed through a discussion of key events comprising oxidative DNA damage, mitochondrial dysfunction, decline in autophagy and lysosomal degradation, as well as senescent cell secretion (SASP), indicating that their reciprocal interactions together define phenotypic features characterizing the aging cell. This network-centric model further mechanistically justifies why peripheral effects of broad-spectrum antioxidant interventions are heterogeneous, and points to rolling back the damage with compensatory quality-control mechanisms and homeostatic regulation as a more effective path toward understanding how to restore homeostasis. These insights may contribute to the development of more precise therapeutic strategies targeting aging-related diseases and improving healthspan. Future research should further clarify the spatiotemporal dynamics of ROS signaling and its integration with cellular stress-response networks. Moreover, elucidating the threshold-dependent and context-specific effects of oxidative signaling may provide a conceptual basis for precision interventions in aging and age-related diseases.

Keywords:  Oxidative stress; aging; cellular senescence; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.1080/10408363.2026.2651307
J Transl Med. 2026 Apr 17. pii: 539. [Epub ahead of print]24(1):

18-β-glycyrrhetinic acid facilitates nuclear-mitochondrial communications to alleviate oxidative stress through HMGB1-cGAS-Mul1 axis in tendinopathy.

Yuan-Yuan Gao, Wen-Shuang Sun, Zi-Ying Sun, Jun-Rui Wang, Zhong-Yang Lv, Yu-Jia Li, Hao-Yuan Tian, Zheng-Yang Bao, Xin-Ran Qiu, Zheng Wang, Shi-Zhong Zheng, Jiang-Juan Shao, Zi-Li Zhang, Jia Meng.

   BACKGROUND: Tendinopathy is a prevalent orthopaedic condition characterized by disrupted tendon homeostasis, with oxidative stress being a key contributing mechanism. Although the natural compound 18-β-Glycyrrhetinic acid (GA) exhibits antioxidant properties and is a therapeutic candidate for tendinopathy, its precise molecular mechanism remains unclear. This study aimed to elucidate how GA alleviates tendinopathy, with a focus on its role in regulating the HMGB1-cGAS-STING axis and NLRP3 inflammasome activation in the context of oxidative stress.
METHODS: We employed single-cell RNA sequencing (scRNA-seq) of clinical samples, proteomics of animal tissues, and comprehensive pharmacological assays to investigate the mechanisms of tendinopathy. Furthermore, the rat tendinopathy model and H2O2-induced oxidative stress model of tendon stem cells (TSCs) were used to validate the protective effects of GA.
RESULTS: We found that GA significantly reduced oxidative stress and subsequent inflammation, thereby mitigating collagen disruption in rats with tendinopathy. Notably, scRNA-seq revealed that the proportion of TSCs increased significantly during tendinopathy, which were particularly susceptible to reactive oxygen species (ROS). TSCs from oxidative damage and inhibited activation of the NLRP3 inflammasome by suppressing the cGAS-STING pathway. Mechanistically, GA promoted cGAS degradation by enhancing its interaction with the mitochondrial E3 ubiquitin ligase Mul1. This effect was mediated through high-mobility group box 1 (HMGB1), as GA disrupted the HMGB1-cGAS interaction. Specifically, GA induced methylation of HMGB1 at lysine 43, a modification essential for its activity. This methylation was catalyzed by the methyltransferase DOT1L, which was upregulated and directly bound by GA. Collectively, GA alleviates tendinopathy by targeting the DOT1L-HMGB1-cGAS axis to resolve oxidative stress and inflammation.
CONCLUSION: Collectively, our findings provide new insights into how oxidative stress accelerates tendinopathy progression. Moreover, they delineate the mechanism by which GA in mitigates oxidative damage and inflammation in TSCs by inhibiting the co-localization of HMGB1 and cGAS. Overall, this study offers scientific support for further developing GA as a promising therapeutic agent for tendinopathy treatment.

Keywords:  18-β-Glycyrrhetinic acid; HMGB1 methylation; NLRP3 inflammasome; Oxidative stress; Tendinopathy; cGAS-STING

DOI:  https://doi.org/10.1186/s12967-026-08091-4
Nutrients. 2026 Mar 24. pii: 1025. [Epub ahead of print]18(7):

Modulation of Glucose Homeostasis, Metabolic Endotoxemia and Circulating Short-Chain Fatty Acids Following Multi-Species Probiotic Supplementation: Findings from a 12-Week Randomised Placebo-Controlled Trial.

George Moschonis, Pauline Dacaya, Thy T Truong, Angela Amoruso, Marco Pane.

  Background: Altered gut microbiota and gut-derived inflammation impair glucose regulation and promote metabolic endotoxemia, yet evidence on probiotic effects across combined glycaemic, inflammatory and short-chain fatty acid (SCFA) outcomes remains limited. This study investigated the effects of a 12-week multi-species probiotic on glucose homeostasis, incretin hormones, inflammatory biomarkers and circulating SCFAs in adults with subthreshold depression. Methods: In a 12-week double-blind, randomised, placebo-controlled trial, 39 adults with subthreshold depression were allocated to either a probiotic supplement containing Limosilactobacillus fermentum LF16, Lacticaseibacillus rhamnosus LR06, Lactiplantibacillus plantarum LP01 and Bifidobacterium longum 04 (n = 19) or placebo (n = 20). Fasting glucose, insulin, HOMA-IR, glucose-dependent insulinotropic peptide (GIP), high-sensitivity C-reactive protein (hs-CRP), lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14) and SCFAs were evaluated at three time points: baseline, week 6 and week 12. Between-group and treatment × time effects were analysed using general linear models. Results: Probiotic supplementation significantly reduced fasting glucose at 12 weeks compared with placebo (-1.8 vs. 0.1 mmol/L; p = 0.036). In the probiotic group, greater reductions in GIP (p = 0.012; p = 0.037), LBP (p < 0.001), sCD14 (p = 0.002; p = 0.001) and hs-CRP (p = 0.047) were also observed compared with placebo. Plasma SCFA concentrations remained largely unchanged, with no significant treatment × time interactions, except for higher valerate levels at 12 weeks in the probiotic group (p = 0.019). Conclusions: Twelve weeks of multi-species probiotic supplementation improved fasting glucose, reduced incretin and inflammatory biomarkers and attenuated metabolic endotoxemia, without alterations in circulating SCFAs. These findings support beneficial modulation of metabolic-immune pathways and highlight the promising role of probiotics to enhance glucose regulation and systemic inflammatory tone in adults with subthreshold depression.

Keywords:  glucose homeostasis; incretin hormones; metabolic endotoxemia; probiotics; short-chain fatty acids

DOI:  https://doi.org/10.3390/nu18071025
Sci Rep. 2026 Apr 11.

DNMT3A drives mitochondrial dysfunction in intracerebral hemorrhage via PGC-1α promoter hypermethylation.

Jun Zhao, Qiongyan Tang, Lu Lu, Minmin Xu, Chunlin Zhang, Ruifang Ren, Ping Zhang, Jing Cao, Weimin Yang.

  Mitochondrial dysfunction drives secondary injury in intracerebral hemorrhage (ICH), yet its upstream regulatory mechanisms remain elusive. This study examines whether ICH-induced DNA methyltransferase 3 A (DNMT3A) activation triggers PGC-1α promoter hypermethylation, causing mitochondrial impairment and neuronal damage through epigenetic silencing of this key metabolic regulator. Both in vitro and in vivo approaches were employed. Primary mouse cortical neurons were treated with hemin (20 µM) to mimic ICH injury. Epigenetic editing using CRISPR-dCas9-DNMT3A, dual-luciferase reporter assays, and chromatin immunoprecipitation were applied to assess locus-specific methylation and promoter activity. In vivo, a collagenase VII-induced striatal ICH model was established in C57BL/6 mice. Interventions included the DNMT3A inhibitor 5-Aza-CdR (1 mg/kg, i.p.) and AAV-shDNMT3A gene therapy. Mitochondrial function (ATP/ROS levels, TEM imaging), gene/protein expression (qPCR/Western blot), promoter methylation (MeDIP-qPCR), and neurobehavioral outcomes (mNSS, rotarod, H&E staining) were evaluated. ICH significantly upregulated DNMT3A expression and activity, leading to hypermethylation of the PGC-1α promoter and transcriptional repression of PGC-1α. This suppression impaired mitochondrial biogenesis (↓TFAM, ↓NRF1) and antioxidant capacity (↓SOD2), resulting in ATP depletion, ROS overproduction, and increased neuronal apoptosis. Both pharmacological inhibition (5-Aza-CdR) and genetic knockdown (AAV-shDNMT3A) of DNMT3A reversed PGC-1α promoter hypermethylation, restored mitochondrial homeostasis, attenuated neuronal apoptosis, and improved functional recovery post-ICH (P < 0.05 vs. ICH group). Our findings demonstrate that DNMT3A promotes PGC-1α promoter hypermethylation, exacerbating mitochondrial dysfunction and brain injury after ICH. Targeted inhibition of DNMT3A mitigates these effects, supporting the DNMT3A-PGC-1α axis as a promising therapeutic target for ICH treatment.

Keywords:  5-Aza-CdR; DNA methyltransferase 3A; Epigenetics; Intracerebral hemorrhage; Mitochondrial dysfunction; PGC-1α

DOI:  https://doi.org/10.1038/s41598-026-47899-4