bims-mistre 2026-07-26 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–07–26
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability.
The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.
Psychological stress induced mitochondrial response in humans and its medial prefrontal biomarker correlates.
MitoQ Ameliorates Diabetic Cardiomyopathy by Inhibiting the mtROS-TXNIP-NLRP3 Pathway.
GDF15: A Novel Insight Into Its Biology and Therapeutic Potential in Obesity.
NAD⁺ biology and supplementation: From mechanisms to clinical perspectives.
VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice.
Targeting mitochondrial dysfunction with traditional Chinese medicine for inflammatory bowel disease: a comprehensive review.
[Research progress on acupuncture-moxibustion regulating brain energy metabolism to intervene in Alzheimer's disease].
Theca cells: active orchestrators of ovarian aging.
A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.
Higher fasting brain glucose is associated with lower gray matter volume in healthy adults.
Mitochondria poor but capacity rich? The paradox of podocyte respiration.
Mitochondrial oxidative stress drives hyperglycaemia-induced contractile dysfunction and arrhythmogenesis in a novel atrial myocyte model of diabetes.
mTOR-Gut Microbiome Interaction in Aging: Fusobacterium nucleatum, Resistance Training and Multi-nutrient Supplementation Effects in Aged Male Rats.
Distinct sources and effects of mitochondrial reactive oxygen species.
Serum anti-Müllerian hormone response to pyrroloquinoline quinone supplementation in healthy women: no overall change and exploratory subgroup findings.
Antidiabetic and Anti-Obesity Effects of Betalains: A Systematic Review of Preclinical Evidence.
Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism.
Magnolol as a promising multitarget agent for Alzheimer's disease: Evidence from a systematic evidence synthesis, network pharmacology, and molecular dynamics simulations.
The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.
Mitochondrial-targeted ROS scavenging by melatonin rescues 1-nitropyrene-induced defects in oocyte quality.
Trimethylamine N-oxide activates cardiac fibroblasts transformation through NLRP3 inflammasome activation with changes in mitochondrial dynamics and ER-mitochondrial contact under ER stress.
Aspirin Inhibits the cGAS-STING Signaling Pathway to Ameliorate the Development of Aortic Aneurysm and Dissection.
Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.

Pharmacol Res. 2026 Jul 19. pii: S1043-6618(26)00260-4. [Epub ahead of print] 108345

Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability.

Rebecca De Lorenzo, Patrizia Rovere-Querini.

  Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.

Keywords:  Aging; Energetic congestion; Frailty; Mitochondrial dysfunction; Pharmacology of aging; Sarcopenia

DOI:  https://doi.org/10.1016/j.phrs.2026.108345
Aging Cell. 2026 Aug;25(8): e70638

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.

Aino Heikkinen, Liina Uusitalo-Kylmälä, Ida Blom, Jørn Wulff Helge, Linn Gillberg, Robert Seaborne, Steen Larsen, Macsue Jacques, Robin Grolaux, Sari Aaltonen, Jaakko Kaprio, Birgitta W van der Kolk, Sini Heinonen, Nir Eynon, Kirsi H Pietiläinen, Riikka Kivelä, Eija Pirinen, Miina Ollikainen.

  Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

Keywords:  epigenetic aging; high‐intensity interval training; mitochondria; nicotinamide riboside; skeletal muscle; twins

DOI:  https://doi.org/10.1111/acel.70638
Transl Psychiatry. 2026 Jul 20.

Psychological stress induced mitochondrial response in humans and its medial prefrontal biomarker correlates.

A Ankeeta, Ashutosh Tripathi, Yizhou Ma, Bindu Pillai, Joshua J Chiappelli, Jennifer N Jernberg, Alia Warner, Keiko Kunitoki, Bhim M Adhikari, Si Gao, Xiaoming Du, Loise Kabui, Francisco Pallares Solano, Oluwabunmi Akindona, Zhenyao Ye, Shuo Chen, Mohammad Milad, Peter Kochunov, Anilkumar Pillai, L Elliot Hong.

Stress response obligates increased mitochondrial activities to meet stress-induced high energy requirement. This stress-mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top-down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress-mitochondrial response paradigm to study the process in humans. We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf-mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress-induced cf-mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS, N = 16), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC (N = 30). We found that salivary cf-mtDNA was significantly elevated immediately after the psychological stress challenge (p = 2.0 × 10-7) and gradually declined after. Exploratory analyses indicated that the cf-mtDNA response was only nominally associated with the cortisol response and was not substantially driven by changes in cortisol. Instead, we found that higher baseline mPFC/dACC lactate+ levels, which may partly reflect mitochondrial dysfunction were significantly associated with the cf-mtDNA response (r = 0.80, p < 0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r = -0.52, p = 0.003). Age had a U-shape effect such that cf-mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct-mtDNA response variance (p = 0.003). This stress challenge-salivary cf-mtDNA assay paradigm may offer a new, non-invasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

DOI: https://doi.org/10.1038/s41398-026-04246-5
Mediators Inflamm. 2026 ;2026(1): e1505350

MitoQ Ameliorates Diabetic Cardiomyopathy by Inhibiting the mtROS-TXNIP-NLRP3 Pathway.

Shaohuan Qian, Junjie Leng, Zhuoya Yao, Chao Shi, Wei Zhang.

   PURPOSE: To determine whether mitoquinone mesylate (MitoQ) could treat diabetic cardiomyopathy (DCM) by inhibiting the mitochondrial reactive oxygen species (mtROS)/thioredoxin (TRX)-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) pathway.
METHODS: In vivo DCM models were established using a high-fat diet combined with streptozotocin injection in mice, whereas in vitro models were generated by exposing AC16 cardiomyocytes to high glucose. Immunohistochemistry (IHC) and western blotting were used to analyze the expression levels of TXNIP, NLRP3, Caspase-1, and other related proteins in cardiac tissue and cardiomyocytes stimulated with high glucose. mtROS fluorescence staining was used to analyze whether MitoQ could alleviate the generation of ROS in mitochondria in a high-glucose environment. Co-IP experiments were used to analyze whether high glucose stimulation promoted the interaction between TXNIP and NLRP3 and induced NLRP3 inflammasome activation.
RESULTS: Diabetic mice exhibited increased oxidative stress, enhanced mtROS accumulation, activation of the TXNIP/NLRP3 inflammasome pathway, myocardial fibrosis, and impaired cardiac function. High-glucose stimulation in AC16 cells promoted dissociation of TXNIP from TRX, enhanced TXNIP-NLRP3 interaction, and increased expression of downstream pyroptosis-related proteins, including NT-gasdermin D (GSDMD), Caspase-1, and cleaved interleukin-1β (IL-1β). MitoQ treatment reduced mtROS production, restored mitochondrial membrane potential (MMP), inhibited TXNIP-NLRP3 interaction, and suppressed inflammasome activation both in vivo and in vitro. Moreover, TXNIP knockdown further enhanced the protective effects of MitoQ, confirming the critical role of the mtROS/TXNIP/NLRP3 axis.
CONCLUSION: MitoQ attenuates diabetic myocardial injury by inhibiting mtROS accumulation and suppressing TXNIP/NLRP3 inflammasome activation. Targeting the mtROS/TXNIP/NLRP3 signaling pathway may represent a promising therapeutic strategy for DCM.

Keywords:  MitoQ; NOD-like receptor protein 3; diabetic cardiomyopathy; thioredoxin-interacting protein

DOI:  https://doi.org/10.1155/mi/1505350
J Diabetes Res. 2026 ;2026(1): e3024772

GDF15: A Novel Insight Into Its Biology and Therapeutic Potential in Obesity.

Kamil Ahmed, Asia Saturnino, Paolo Pozzilli.

  Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has recently been identified as a key regulator of appetite homeostasis. Although GDF15 was previously regarded as only a biomarker of disease burden, the discovery of its exclusive receptor, GFRAL, repositioned it as a key mediator of sickness-associated anorexia. The clinical significance of GDF15 and its receptor, GFRAL, is supported by evidence that established weight-loss agents influence circulating GDF15 levels and that GDF15 agonists induce marked weight loss in both preclinical and early-phase clinical studies. This review integrates recent advances in GDF15 biology from evolutionary, mechanistic and translational perspectives, with particular emphasis on its emerging therapeutic potential in obesity.

Keywords:  body weight; cellular stress signalling; growth differentiation factor 15 (GDF15); obesity; therapy

DOI:  https://doi.org/10.1155/jdr/3024772
Mol Biol Rep. 2026 Jul 23. pii: 1249. [Epub ahead of print]53(1):

NAD⁺ biology and supplementation: From mechanisms to clinical perspectives.

Sergio Pandolfi, Charlye Ghezzi, Geir Björklund, Marco Metalla, Francesco Maria Paone, Salvatore Chirumbolo.

  This study examines the biological and clinical relevance of NAD⁺ supplementation using a combined review and mathematical modelling approach. NAD⁺ plays a central role in cellular energy metabolism, redox balance, and signaling pathways linked to aging, neurodegeneration, and metabolic health. Current evidence shows that oral NAD⁺ precursors such as nicotinamide riboside and nicotinamide mononucleotide can increase circulating NAD⁺ levels, although their clinical benefits remain variable and context-dependent. Intravenous NAD⁺ administration is less well characterized and lacks robust clinical validation. The modelling framework presented here highlights that NAD⁺ responses are nonlinear and influenced by factors such as dose, age, metabolic state, and route of administration. Rather than following a simple dose-response relationship, NAD⁺ supplementation appears to operate within a complex regulatory system involving feedback mechanisms and biological saturation. Overall, these findings emphasize the need for cautious interpretation of current data and for well-designed clinical studies to define effective and safe therapeutic strategies.

Keywords:  Doses; Infusion; NAD; Nutraceuticals; Pharmacokinetics

DOI:  https://doi.org/10.1007/s11033-026-12351-3
Geroscience. 2026 Jul 22.

VCD-induced estropause fails to enhance responsiveness to 17α-estradiol in adult female mice.

Sean R Janovic, Roberto Santín-Márquez, José V V Isola, Camila R C de Brito, Roshini Sathiaseelan, Jessica D Hense, Subhasri Biswas, Heather C Rice, Samim A Mondal, Michael B Stout.

  17α-estradiol (17α-E2) extends median lifespan and improves metabolic homeostasis in male mice through estrogen receptor α (ERα)-dependent mechanisms, but female mice are largely unresponsive unless ovariectomized or subjected to chronic high-fat feeding. Whether the gradual hormonal transition of natural reproductive aging similarly unmasks female responsiveness to 17α-E2 remains unknown. We tested whether 4-vinylcyclohexene diepoxide (VCD)-induced depletion of the ovarian reserve would render female mice responsive to 17α-E2 by treating wild-type (WT) and ERα knockout (ERαKO) littermates with VCD followed by 16 weeks of 17α-E2 administration. VCD-induced estropause was confirmed by elevated FSH, anestrus, and reduced ovarian size, but did not adversely affect metabolic phenotypes in WT mice. 17α-E2 treatment elicited modest improvements in adiposity and glucose tolerance, suppressed circulating IL-1β and IL-6, and reversed estropause-induced uterine atrophy in WT mice, but failed to rescue endometrial fibrosis. All 17α-E2-mediated effects were absent in ERαKO mice. These findings demonstrate that estropause does not unmask broad female responsiveness to 17α-E2 and indicate that the sex-specific actions of 17α-E2 extend beyond competitive receptor occupancy by endogenous 17β-E2.

Keywords:  17α-estradiol; Estrogen receptor α; Estropause; Menopause; Ovary; Uterus

DOI:  https://doi.org/10.1007/s11357-026-02434-1
Front Pharmacol. 2026 ;17 1851055

Targeting mitochondrial dysfunction with traditional Chinese medicine for inflammatory bowel disease: a comprehensive review.

Linxi Zeng, Yao Huang, Jiayi Ke, Jiaqi Han, Wenda Xie, Zhishan Ding, Fangmei Zhou.

  Inflammatory Bowel Disease (IBD) is a chronic relapsing inflammatory condition of the intestine, characterized by symptoms such as chronic diarrhea, abdominal pain, and weight loss. The pathogenesis of IBD is complex, with mitochondrial dysfunction being considered a key factor in its onset, progression, and persistence. Mitochondria, as the primary energy suppliers within cells, not only produce adenosine triphosphate (ATP) but also play crucial roles in regulating cellular metabolism, maintaining redox balance, and controlling cell death processes. Targeting mitochondria to regulate mitochondrial functions, including energy metabolism, oxidative stress, mitophagy, dynamics, and biogenesis, as well as maintaining the dynamic balance of the "gut microbiota-mitochondria axis," has emerged as a promising strategy for the prevention and treatment of IBD. Traditional Chinese Medicine (TCM) has shown potential multi-target regulatory properties in preclinical studies; however, robust clinical validation and target-specific pharmacological evidence remain limited. This review explores the mechanisms and underlying connections between mitochondrial dysfunction and IBD, summarizing the current research on how active metabolites of TCM modulate mitochondrial dysfunction in the prevention and treatment of IBD. It provides new insights into the pathogenesis of the disease and opens up new avenues and strategies for the prevention, treatment, and research on IBD treatment with TCM.

Keywords:  Crohn’s disease; inflammatory bowel disease; mitochondrial dysfunction; traditional Chinese medicine; ulcerative colitis

DOI:  https://doi.org/10.3389/fphar.2026.1851055
Zhen Ci Yan Jiu. 2026 Jul 25. pii: 1000-0607(2026)07-0923-10. [Epub ahead of print]51(7): 923-932

[Research progress on acupuncture-moxibustion regulating brain energy metabolism to intervene in Alzheimer's disease].

Li Li, Chang Hong, Wen-Ting Xie, Ren-Zhen Zhang, Yu-Ting Wei, Cui Ma, Xing-Ke Yan.

  Alzheimer's disease (AD) is a common neurodegenerative disorder, and brain energy metabolism disorders are closely related to the onset of AD. Acupuncture-moxibustion is one of the effective treatments for AD, which can significantly improve AD symptoms and slow down the progression of the disease. The mechanism of its action has also been continuously studied. This article summarizes the relevant research on acupuncture-moxibustion regulating brain energy metabolism to improve AD. The results show that acupuncture-moxibustion mainly improves AD brain energy metabolism disorders from the following aspects: 1) regulating glucose metabolism disorders (promoting glucose transport, increasing glucose uptake and utilization, and regulating glycolytic activity in the brain), 2) regulating mitochondrial structure and dysfunction (improving mitochondrial structure and dynamics, enhancing electron transfer chain activity and ATP production, inhibiting abnormal opening of mitochondrial permeability transition pores), 3) improving insulin resistance and damage to the insulin signaling pathway, and 4) restoring amino acid and lipid metabolic imbalance. It plays a role in neuroprotection and delaying the progression of the disease.

Keywords:  Acupuncture-moxibustion; Alzheimer’s disease; Energy metabolism; Review

DOI:  https://doi.org/10.13702/j.1000-0607.20250813
Reprod Biol Endocrinol. 2026 Jul 20.

Theca cells: active orchestrators of ovarian aging.

Hongbo Wu, Zhao Zhang, Qianyi Huang, Bo Liu, Lidan Liu.

  Ovarian aging is characterized by the progressive depletion of the follicular reserve and deterioration of reproductive endocrine function, yet its cellular basis has been disproportionately attributed to oocyte and granulosa cell decline. Theca cells - the principal androgen-producing cell type of the ovarian follicle - have remained critically underappreciated in this context. Operating through the classical two-cell, two-gonadotropin model, theca cells supply androgen precursors that granulosa cells aromatize into estradiol, and their dysfunction therefore impairs estrogen biosynthesis irrespective of granulosa cell competence. During ovarian aging, theca cells undergo quantitative decline, transcriptional reprogramming, and progressive steroidogenic impairment. Single-cell transcriptomic analyses reveal age-dependent upregulation of senescence pathways - including CDKN1A, NF-κB, and SASP-associated factors - alongside downregulation of FOXP1, a transcription factor that normally suppresses cellular senescence through direct repression of CDKN1A. Senescent theca-interstitial cells elaborate pro-inflammatory mediators, most notably CCL5, TNF-α, IL-1β, and IL-6, which suppress steroidogenic gene expression, induce granulosa cell apoptosis, and promote ovarian fibrosis, collectively accelerating follicular atresia. At the molecular level, mitochondrial dysfunction driven by aberrant GSK3β activation impairs oxidative phosphorylation and steroidogenic capacity, while dysregulation of the PTEN/PI3K/Akt/FOXO1 axis uncouples theca cells from LH-dependent gonadotropin signaling. Theca cell dysfunction further underlies distinct clinical entities, including premature ovarian insufficiency, diminished ovarian reserve, and polycystic ovary syndrome. Emerging therapeutic strategies - encompassing mesenchymal stem cell-derived exosomes, senolytics, mitochondria-targeted interventions, and Wnt/β-catenin pathway modulation - have demonstrated efficacy in restoring theca cell function in preclinical models. This review repositions theca cells as active, bidirectionally regulated participants in ovarian aging-integral to, rather than upstream of, the oocyte-granulosa-theca unit-and proposes theca-specific biomarkers and targeted interventions as priorities for future translational research.

Keywords:  Cellular senescence; Ovarian aging; Premature ovarian insufficiency; Steroidogenesis; Theca cells

DOI:  https://doi.org/10.1186/s12958-026-01593-2
Alzheimers Dement. 2026 Jul;22(7): e71605

A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.

Christopher R Martens, Kevin P Decker, Theodore M DeConne, Faria Sanjana, Fiona Horvat, Nicholas A Rizzi, Catherine Awad, Elizabeth Habash, Joshua C Hobson, Mary K Kramer, Michael L Armstrong, Nichole Reisdorph, Ryan T Pohlig, Alyssa M Lanzi, Curtis L Johnson, Matthew L Cohen, James M Ellison.

   INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD+) may elevate risk of Alzheimer's disease.
METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD+ precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).
RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD+ increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). Exploratory analyses revealed potential increases in regional CBF, particularly in the hippocampus.
DISCUSSION: NR effectively raises NAD+ in people with MCI but does not improve cognitive function, total CBF, or blood pressure over 12 weeks. Future studies should investigate regional effects on CBF over longer treatment durations.

Keywords:  NAD+; cerebral blood flow; clinical trial; mild cognitive impairment; nicotinamide riboside

DOI:  https://doi.org/10.1002/alz.71605
J Cereb Blood Flow Metab. 2026 Jul 19. 271678X261444882

Higher fasting brain glucose is associated with lower gray matter volume in healthy adults.

Helena van Nieuwenhuizen, Botond B Antal, Antoine Hone-Blanchet, Andrew Lithen, Liam McMahon, Bruce G Jenkins, Eva-Maria Ratai, Lilianne R Mujica-Parodi.

  Glucose hypometabolism is implicated in age-related neurodegeneration, with peripheral markers such as hyperglycemia and insulin resistance linked to increased dementia risk and brain atrophy. However, the degree to which peripheral and cerebral glucose dysregulation are coupled remains unclear. To address this, we used ultra-high-field 1H MRS to directly quantify fasting brain glucose concentrations in the posterior cingulate cortex of 47 healthy adults from across the lifespan, with concurrent structural MRI and fasting blood glucose measurements. We found that both fasting blood and brain glucose increase with age but follow distinct trajectories: peripheral glucose rises significantly by midlife (40-60 years) and then plateaus, whereas cerebral glucose remains stable until older age (60-80 years) before increasing. Furthermore, brain glucose, but not blood glucose, independently predicts gray matter loss and partially mediates age-related atrophy, with effects strongest in subcortical, GLUT4-expressing regions. Our results provide direct in vivo evidence that higher fasting brain glucose levels are associated with age-related gray matter loss, and suggest a delayed trajectory compared to peripheral glucose elevation, consistent with cerebral metabolic prioritization. Brain glucose measured by MRS represents a promising biomarker of metabolic dysfunction that may enable early detection of neuronal vulnerability and inform interventions targeting brain-specific glucose metabolism.

Keywords:  Aging; MRS; atrophy; glucose; metabolism

DOI:  https://doi.org/10.1177/0271678X261444882
Kidney Int. 2026 Aug;pii: S0085-2538(26)00427-8. [Epub ahead of print]110(2): 291-293

Mitochondria poor but capacity rich? The paradox of podocyte respiration.

Antonio S Novaes, Ilse S Daehn.

Campbell et al. show that podocyte mitochondria, isolated using a cell-specific MITO-Tag approach, possess high intrinsic respiratory capacity despite their low abundance. The study demonstrates that conventional culture conditions suppress mitochondrial respiration and increase oxidative stress, suggesting that current experimental systems may underestimate mitochondrial function in podocytes. The authors provide evidence that mitochondrial respiratory capacity in podocytes declines in male mice with aging, indicating that mitochondria could play a role in age-associated glomerular injury.

DOI: https://doi.org/10.1016/j.kint.2026.05.008
Biochim Biophys Acta Mol Basis Dis. 2026 Jul 21. pii: S0925-4439(26)00236-X. [Epub ahead of print]1872(8): 168373

Mitochondrial oxidative stress drives hyperglycaemia-induced contractile dysfunction and arrhythmogenesis in a novel atrial myocyte model of diabetes.

Alexia van Rinsum, Liangyu Hu, Xi Qi, Gül Turan, Juan Zhang, Sven Olaf Dekker, Antoine A F de Vries, Jaap Keijer, Deli Zhang.

  Diabetes mellitus (DM)-induced cardiac arrhythmia involves complex pathophysiological processes, in which mitochondrial dysfunction and mitochondrial oxidative stress are recognized as central mediators. Recently, conditionally immortalized rat atrial myocyte lines (iAMs) were developed, allowing doxycycline-dependent switching between proliferative and contractile states. These iAMs offer a promising model for studying atrial arrhythmias and dysfunction. Whether these cells can be used as a model to study diabetes-induced mitochondrial dysfunction, and whether this is a viable target for prevention, remains unclear. To study this, we firstly characterized the mitochondrial function in iAMs and found that high glucose (HG) treatment of differentiated iAMs induced a diabetic state marked by mitochondrial dysfunction, production of reactive oxygen species, and (mitochondrial) oxidative stress, which were associated with contractile dysfunction and arrhythmogenesis. These HG-induced changes were prevented by the mitochondria-targeted antioxidant, MitoTEMPO. Findings were validated in an in vivo diabetic Drosophila model. Taken together, we established HG-treated iAMs as a model for diabetes-related cardiac arrhythmias and dysfunction, as well as for screening of therapeutic interventions, and identified mitochondrial oxidative stress as a potential therapeutic target.

Keywords:  Cardiac arrhythmia; Diabetes; Drosophila; Mitochondrial dysfunction; Mitochondrial oxidative stress; iAMs

DOI:  https://doi.org/10.1016/j.bbadis.2026.168373
FASEB J. 2026 Jul 31. 40(14): e72129

mTOR-Gut Microbiome Interaction in Aging: Fusobacterium nucleatum, Resistance Training and Multi-nutrient Supplementation Effects in Aged Male Rats.

Majid Mohabbat, Mona Nouri, Hamid Arazi.

  We investigated the mTOR pathway in relation to gut microbiome composition and Fusobacterium nucleatum (Fn) in aged male Wistar rats undergoing resistance exercise and multi-nutrient supplementation. Thirty-five male rats (OC, YC, OS, OR, ORS; n = 7/group) underwent 8-week moderate-intensity resistance training and/or supplementation (Lactobacillus plantarum, Bifidobacterium bifidum, vitamin D, leucine). Muscle samples were analyzed by RT-PCR and Western blot; fecal DNA by 16S rRNA sequencing (p < 0.05). Finding revealed significant increases in the mTOR/IGF-1/S6K1 protein content and gene expression in the ORS group compared to OS and OR groups (mTORC1: ORS vs. OR, p = 0.011; ORS vs. OS, p < 0.001; IGF-1: ORS vs. OR, p = 0.008; ORS vs. OS, p = 0.001), which showed only mild increases. The F/B ratio decreased in all intervention groups, with ORS reaching levels comparable to YC (p = 0.207). Resistance training alone did not significantly affect Fn, but the ORS group had the lowest Fn levels, comparable to YC (p = 0.069) and significantly lower than OR and OS (p = 0.001). The study provides novel evidence that combined resistance training and multi-nutrient supplementation (L. plantarum, B. bifidum, vitamin D, leucine) upregulates mTOR/IGF-1/S6K1 signaling and reduces Fusobacterium nucleatum in aged male rats. The ORS group outperformed either intervention alone; Fn correlates strongly with S6K1 (r = -0.85) and IGF-1 (r = -0.81), supporting the gut-muscle axis as a therapeutic target for sarcopenia.

Keywords:   Fusobacterium nucleatum ; aging; firmicutes/Bacteroidetes ratio; gut microbiome; mTOR; probiotics; resistance training; sarcopenia

DOI:  https://doi.org/10.1096/fj.202504395R
Mol Cell. 2026 Jul 24. pii: S1097-2765(26)00473-9. [Epub ahead of print]

Distinct sources and effects of mitochondrial reactive oxygen species.

Daniel Barnett, Caroline Booraem, Anna G Orr, Adam L Orr.

  Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.

Keywords:  cell metabolism; cell signaling pathways; complex I; complex III; disease mechanisms; electron leak; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.molcel.2026.07.009
Front Endocrinol (Lausanne). 2026 ;17 1831604

Serum anti-Müllerian hormone response to pyrroloquinoline quinone supplementation in healthy women: no overall change and exploratory subgroup findings.

Saori Tsuji, Tsuyoshi Takiuchi, Mika Handa, Naoki Miura, Hisae Aoyagi, Yuki Uematsu, Miwako Shidomi, Kazutake Fukada, Chiaki Ogura, Tadashi Kimura, Michiko Kodama.

   Introduction: Oocyte maturation requires substantial ATP, and the resulting oxidative stress may impair follicular development. Pyrroloquinoline quinone (PQQ), an antioxidant compound, protects mitochondria and promotes follicular development in animal models; however, its effects on human ovarian function remain unclear.
Methods: This single-arm, open-label study prospectively evaluated the effects of oral PQQ supplementation on ovarian reserve and related clinical and biochemical outcomes. The primary outcome was serum anti-Müllerian hormone (AMH). Secondary outcomes included luteinizing hormone, follicle-stimulating hormone, estradiol, biological antioxidant potential, reactive oxygen metabolites-derived compounds (d-ROMs), and Menstrual Distress Questionnaire (MDQ) scores. Fifty healthy women aged 25-42 years with regular menstrual cycles and baseline serum AMH levels of 0.5 ≤ AMH < 3.0 ng/mL received 20 mg/day of PQQ for 90 ± 10 days. Blood samples were collected on menstrual cycle days 1-7 before and after supplementation. Exploratory subgroup analyses were performed using combined stratification by age and baseline AMH.
Results: Analyses were conducted in the per-protocol set (n = 35). AMH did not change significantly overall (1.561 ± 0.689 vs. 1.439 ± 0.772 ng/mL, p = 0.182). In younger participants with lower baseline AMH (n = 7), AMH showed a non-significant increase (1.121 ± 0.379 vs. 1.361 ± 0.604 ng/mL, p = 0.056), accompanied by a significant decrease in d-ROMs (351.3 ± 43.5 vs. 305.3 ± 34.3 U. CARR, p = 0.027). In contrast, older participants with lower baseline AMH (n = 13) showed a significant decrease in AMH (1.066 ± 0.296 vs. 0.852 ± 0.312 ng/mL, p = 0.033), while d-ROMs remained unchanged. Across the overall cohort, d-ROMs showed a non-significant reduction (334.2 ± 59.7 vs. 321.5 ± 63.9 U. CARR, p = 0.090).
Conclusion: PQQ supplementation did not alter AMH levels in the overall cohort. Subgroup findings were inconsistent and should be interpreted cautiously given the small sample sizes and absence of a control group. These exploratory results do not permit conclusions regarding clinical efficacy. Larger, placebo-controlled trials with imaging-based and clinical reproductive endpoints are needed to determine whether PQQ has measurable effects on ovarian biology.
Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000056669, identifier UMIN000049793.

Keywords:  anti-Müllerian hormone (AMH); follicular development; ovarian reserve; oxidative stress; pyrroloquinoline quinone (PQQ); reproductive health

DOI:  https://doi.org/10.3389/fendo.2026.1831604
Mol Nutr Food Res. 2026 Jul;70(14): e70552

Antidiabetic and Anti-Obesity Effects of Betalains: A Systematic Review of Preclinical Evidence.

Ahmad Mujtaba Noman, Muhammad Tauseef Sultan, Aroob Fatima, Zoha Saleem, Naima Tariq, Hassan Raza.

  Metabolic disorders like diabetes and obesity represent major global health challenges, largely driven by unhealthy dietary patterns and sedentary lifestyles. Growing interest in natural bioactives as complementary strategies is increasing. Betalains, primarily derived from Beta vulgaris, exhibit notable antidiabetic and anti-obesity properties, highlighting their therapeutic potential. This systematic review evaluates the antidiabetic and anti-obesity effects of betalains based on in vitro and in vivo evidence. Literature published between 2015 and 2025 was retrieved from PubMed, ScienceDirect, Scopus, Web of Science, and Google Scholar. Eligible studies assessed betalains effects on glucose and lipid metabolism, while reviews and irrelevant reports were excluded. Out of 508 identified studies, only 12 met the inclusion criteria. The systematic review was registered in PROSPERO under ID 1357942. Risk of bias was assessed using the OHAT tool for in vitro studies and the SYRCLE tool for animal studies. Betalains demonstrated significant metabolic benefits by reducing triglyceride accumulation, fasting blood glucose, insulin resistance, and NF-κB activation, while increasing insulin, adiponectin, and HDL-C levels. They also downregulated total cholesterol, LDL-C, and lipogenic markers (PPARγ, SREBP-1c). Overall, betalains show potential as natural agents against diabetes and obesity; however, well-designed clinical trials with standardized dosing are needed to confirm long-term efficacy.

Keywords:  betalains; betanin; diabetes; glucose metabolism; insulin resistance; obesity; preclinical studies

DOI:  https://doi.org/10.1002/mnfr.70552
iScience. 2026 Jul 17. 29(7): 116442

Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism.

Esther Paulo, Yuanyuan Wu, Biao Wang.

  Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat production depends on oxygen-driven mitochondrial activity. To define the role of complex IV, we generated brown-adipocyte-specific Cox10-knockout mice (Cox10BKO), as Cox10 is required for cytochrome c oxidase assembly. Cox10-deficient brown adipocytes exhibited markedly reduced complex IV activity and impaired Ucp1-dependent thermogenesis. Although ATF4 signaling was strongly induced, the alternative ATF4-dependent thermogenic pathway failed due to suppression of global protein synthesis, consistent with severe mitochondrial stress and reduced ribosomal gene expression. Unexpectedly, Cox10BKO mice housed at room temperature or thermoneutrality were protected against high-fat-diet-induced obesity and insulin resistance. These findings demonstrate that brown adipocytes regulate systemic metabolic homeostasis independently of canonical thermogenic function and suggest that respiration-deficient brown fat may promote metabolic fitness through endocrine or metabolic signaling mechanisms.

Keywords:  human metabolism; metabolic flux analysis; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.116442
Phytomedicine. 2026 Jul 14. pii: S0944-7113(26)00817-2. [Epub ahead of print]159 158586

Magnolol as a promising multitarget agent for Alzheimer's disease: Evidence from a systematic evidence synthesis, network pharmacology, and molecular dynamics simulations.

Yiying Qin, Xiaoyu Dong, Chong Zhang, Jianfei Nao.

   OBJECTIVE: This study provides systematic synthesis of therapeutic effects of magnolol (MN) in preclinical Alzheimer's disease (AD) models and integrates network pharmacology with molecular dynamics (MD) simulations to predict its core targets and binding stability.
METHODS: Systematic literature search was conducted in PubMed, CNKI, Wanfang, and Google Scholar up to January 1, 2026 following PRISMA guidelines. Network pharmacology, molecular docking, and 100 ns MD simulations were used to identify common targets, evaluate binding affinities, and assess complex stability.
RESULTS: Fourteen studies (seven in vivo, five in vitro, two combined) were included. MN consistently ameliorated cognitive deficits and neuropathology through antioxidant, anti-inflammatory, anti-apoptotic, and anti-acetylcholinesterase activities, while preserving mitochondrial and synaptic function. Network pharmacology identified 60 common targets; Protein-Protein Interaction (PPI) analysis revealed five hub genes: AKT1, MMP9, MMP2, ERBB2, and EGFR. Molecular docking showed binding energies below -4.0 kcal/mol for all five targets, and MD simulations confirmed stable binding, with the ERBB2-MN complex exhibiting the lowest root mean square deviation (RMSD) (1.2 Å) and favorable free energy landscape. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations further confirmed that magnolol exhibited binding affinities comparable to the reference co‑crystal ligands. Unlike prior reviews, this study uniquely combines systematic evidence synthesis with computational predictions, identifying ERBB2 as a novel stable target of MN.
CONCLUSION: MN exerts anti-AD effects via multi-pathway and multi-target regulation, with computational predictions aligning with experimental evidence, supporting MN as promising lead compound for AD drug development.

Keywords:  Alzheimer’s disease; Magnolol; Molecular dynamics simulation; Network pharmacology; Neuroprotection

DOI:  https://doi.org/10.1016/j.phymed.2026.158586
Biochem Biophys Res Commun. 2026 Jul 16. pii: S0006-291X(26)01068-5. [Epub ahead of print]831 154304

The mitochondrial DNA signal in rheumatoid arthritis: From metabolic victim to inflammatory driver.

Ruoyi Zhang, Zhijie Song, Qimeng Xin, Wenbin Xing, Wenlan Zhang, Yanmei Yang.

  Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by sustained immune activation and profound metabolic dysregulation. Accumulating evidence indicates that mitochondrial DNA (mtDNA) plays an active role in linking mitochondrial stress to innate immune signaling in RA. This review synthesizes current findings within a unifying mechanistic framework centered on the mtDNA damage-release-immune activation axis. Owing to limited chromatin protection and constrained repair capacity, mtDNA is highly susceptible to oxidative injury in the inflammatory microenvironment of RA, leading to copy number alterations and mutational accumulation. Damaged or oxidized mtDNA can translocate to the cytosol or extracellular space, where it acts as an immunostimulatory danger signal and amplifies innate immune activation. Persistent mtDNA-related signaling, together with oxidative stress and impaired mitochondrial quality control, contributes to immunometabolic reprogramming in key effector populations. Clinically, circulating cell-free mitochondrial DNA has emerged as a dynamic biomarker associated with disease activity and therapeutic response. Collectively, this framework integrates mitochondrial dysfunction with immune activation in RA and highlights mtDNA-centered pathways as rational targets for mechanism-based intervention. Further standardization of mtDNA assays and mechanism-informed clinical studies will be essential to advance mtDNA-focused precision strategies in RA.

Keywords:  Immunometabolism; Mitochondrial DNA; NLRP3 inflammasome; Rheumatoid arthritis; TLR9; cGAS-STING

DOI:  https://doi.org/10.1016/j.bbrc.2026.154304
Ecotoxicol Environ Saf. 2026 Jul 18. pii: S0147-6513(26)00837-7. [Epub ahead of print]322 120507

Mitochondrial-targeted ROS scavenging by melatonin rescues 1-nitropyrene-induced defects in oocyte quality.

Fei Wu, Yiwei Zhang, Huimin Qu, Hong Chen, Fei Huang, Jiaze Gao, Zhonghua Liu, Jun-Xue Jin, Di Fang.

  As a prevalent and highly toxic environmental contaminant, 1‑nitropyrene (1‑NP) poses a significant threat to reproductive health, embryonic development, and genomic integrity. However, the specific mechanisms by which it impairs oocyte quality remain incompletely understood. Melatonin, a potent free‑radical scavenger, has been shown to protect the reproductive system from oxidative damage. In this study, we investigated the deleterious effects of 1‑NP on mouse oocytes and evaluated the potential of melatonin to counteract such toxicity. Our results demonstrate that 1‑NP exposure severely compromises oocyte maturation, fertilization, and subsequent preimplantation development. Transcriptomic sequencing revealed that 1‑NP dramatically alters the oocyte gene expression profile, leading to defective clearance of maternally inherited mitochondrial transcripts. This disruption subsequently induces mitochondrial dysfunction and oxidative stress. In parallel, 1‑NP treatment also perturbed key epigenetic modifications. In contrast, melatonin co‑treatment effectively ameliorated 1‑NP‑induced meiotic spindle anomalies, chromosomal aneuploidy, mitochondrial dysfunction, oxidative stress, and epigenetic aberrations, thereby restoring oocyte quality and post‑fertilization developmental competence. Notably, melatonin reversed the majority of the aberrant gene expression patterns elicited by 1‑NP. Strikingly, treatment with the mitochondria‑targeted antioxidant Mito‑TEMPO alone in the 1‑NP exposure system significantly improved oocyte maturation rates, restored mitochondrial membrane potential, and reduced ROS levels. Together, these findings indicate that melatonin protects mouse oocytes from 1‑NP‑induced damage primarily by targeting mitochondria and clearing mitochondrial ROS, thereby alleviating oxidative stress and revealing a promising therapeutic strategy against environmental reproductive toxicants.

Keywords:  1-NP; Epigenetic; Melatonin; Mitochondrial; Mito‑TEMPO; Oocyte

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120507
Mol Cell Biochem. 2026 Jul 20.

Trimethylamine N-oxide activates cardiac fibroblasts transformation through NLRP3 inflammasome activation with changes in mitochondrial dynamics and ER-mitochondrial contact under ER stress.

Huimin Wang, Hanlin Liu, Xinnan Meng, Jiantao Song, Yan Jin, Yuanyuan Bai.

  Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been linked to cardiovascular diseases. This study aimed to explore the role of TMAO in cardiac fibrosis by examining its effects on the NLRP3 inflammasome, endoplasmic reticulum stress (ERS), mitochondria-associated membranes (MAMs), and mitochondrial dynamics in cardiac fibroblasts (CFs), alongside clinical data from acute myocardial infarction (AMI) patients and unstable angina (UA) patients and AMI animal model data. Plasma TMAO levels were measured in AMI patients and healthy controls. In vitro, CFs were treated with TMAO to assess cellular activation and fibrosis markers. Western blot, immunofluorescence, and RNA sequencing identified key pathways and proteins related to ERS, NLRP3 inflammasome activation, and mitochondrial dynamics. In vivo, Masson's trichrome staining, Hematoxylin-Eosin (HE) staining and Immunohistochemical were used to evaluate the effects of TMAO on AMI mice. Plasma TMAO levels were significantly higher in the AMI group. TMAO promoted cardiac fibroblast activation and fibrosis by increasing α-SMA and Collagen I expression. It induced ERS, marked by elevated GRP78, p-PERK, and CHOP, and upregulated Sigma-1R, enhancing MAM formation. TMAO also altered mitochondrial dynamics via DRP1 phosphorylation and Mfn2 expression. RNA sequencing identified macrophage migration inhibitory factor (MIF) as a key mediator linking TMAO to NLRP3 inflammasome activation. TMAO exacerbates myocardial injury and fibrotic remodeling in AMI mice. TMAO exacerbates cardiac fibrosis via ERS and NLRP3 activation, with implications for mitochondrial dynamics and MAM formation. Elevated TMAO levels in AMI patients underscore its potential as a therapeutic target for ventricular remodeling fibrosis.

Keywords:  Cardiac fibroblasts; Endoplasmic reticulum stress; MAMs; MIF; NLRP3; TMAO

DOI:  https://doi.org/10.1007/s11010-026-05658-z
Arterioscler Thromb Vasc Biol. 2026 Jul 23.

Aspirin Inhibits the cGAS-STING Signaling Pathway to Ameliorate the Development of Aortic Aneurysm and Dissection.

Yi-Fan Zeng, Qiu-Guo Wang, Zhen Qi, Jing-Yu Li, Zhi-Cheng Duan, Wen-Jing Zeng, Ye-Rong Hu, Ling Tan, Hao Tang.

   BACKGROUND: Aortic aneurysm and dissection (AAD) is a life-threatening vascular disease that currently lacks effective pharmacological therapies. Clinical evidences suggest that aspirin may exert a protective effect on AAD, but the underlying molecular mechanism is still unclear at present.
METHODS: Three mouse animal models of AAD and H2O2-induced ferroptosis model in human aortic vascular smooth muscle cells were established. On this basis, RNA sequencing was performed to investigate potential molecular mechanisms, and further experiments were conducted using STING (stimulator of interferon genes) agonist to confirm the mechanisms.
RESULTS: Aspirin was found to ameliorate the progression of AAD in the β-aminopropionitrile and CaPO4 mouse models. Interestingly, aspirin reduced mortality in mice but did not reduce the incidence of AAD in the β-aminopropionitrile + angiotensin II model. Furthermore, aspirin inhibited H2O2-induced ferroptosis in human aortic vascular smooth muscle cells and suppressed activation of cGAS (cyclic GMP-AMP synthase)-STING signaling pathway. Activation of STING with STING agonist markedly increased STING, TBK1 (TANK-binding kinase 1), and IRF3 (interferon regulatory factor 3) phosphorylation and abolished the protective effect of aspirin against H2O2-induced ferroptosis in human aortic vascular smooth muscle cells. Western blot and immunofluorescence results indicated significant activation of the cGAS-STING signaling pathway following treatment with STING agonist. Coimmunoprecipitation analysis revealed that cGAS acetylation was considerably enhanced in human aortic vascular smooth muscle cells after aspirin treatment. Additionally, administration of aspirin and dimeric amidobenzimidazole compound 3 showed that dimeric amidobenzimidazole abolished the protective effect of aspirin in the CaPO4 model. Coimmunoprecipitation results indicated that aspirin promoted cGAS acetylation in mouse aortic tissue. Western blot and immunohistochemistry results also confirmed that the dimeric amidobenzimidazole compound 3 activated phosphorylation of STING, TBK1, and IRF3 and significantly negatively regulated the expression of GPX4. In the β-aminopropionitrile model, dimeric amidobenzimidazole also abolished the protective effect of aspirin.
CONCLUSIONS: Aspirin confers a protective effect against AAD by promoting cGAS acetylation and inhibiting the cGAS-STING signaling pathway and ferroptosis in VSMC.

Keywords:  aortic aneurysm; aortic dissection; aspirin; ferroptosis; interferon

DOI:  https://doi.org/10.1161/ATVBAHA.126.324930
Smart Med. 2026 Jun;5(3): e70043

Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.

Yixiang Zhang, Yawei Du, Shifeng Ling, Hanqi Wang, Jiahao He, Jiahong Li, Kaifeng Huo, Baikun Liu, Qingfeng Li, Jiao Wei, Wenguo Cui.

  Adipose-derived stem cells (ADSCs) are central regulators of adipose tissue homeostasis and regenerative capacity. Accumulating evidence indicates that aging and obesity profoundly impair ADSC function, through progressive mitochondrial dysfunction and disrupted mitochondrial-nuclear communication. Emerging studies reveal that defects in nuclear-mitochondrial crosstalk constitute a key driver of ADSC senescence and adipose tissue aging. In this review, we synthesize recent advances in understanding the mitochondrial mechanisms underlying ADSC aging, with particular emphasis on how mitochondrial dysfunction reshapes stem cell fate decisions, metabolic plasticity, and inflammatory signaling within aged adipose niches. We further highlight mitochondria targeting therapeutic strategies that hold promise for reversing ADSC senescence. Collectively, this framework positions mitochondrial regulation as a unifying axis for ADSC rejuvenation, offering new opportunities to restore adipose tissue homeostasis and mitigate age-related metabolic dysfunction.

Keywords:  adipose derived stem cell; aging; cellular communication; mitochondria; mtDNA

DOI:  https://doi.org/10.1002/smmd.70043