bims-mistre 2026-06-28 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–06–28
twenty-two papers selected by
Ellen Siobhan Mitchell, MitoQ

Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.
Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
Mitochondrial oxidative stress promotes the accumulation of advanced glycation end products.
Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
A combination of ketones and NAD+ precursor preserves white matter integrity in mild cognitive impairment.
Effects of Physical Exercise with and Without Nutritional Supplementation on Serum Albumin in Older People: A Systematic Review and Meta-Analysis.
Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.
The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.
Metabolism of the antioxidant micronutrient ergothioneine as a plasma biomarker of cognitive resilience in older people with Alzheimer's disease amyloid pathology.
Why diabetes matters in dementia studies: Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.
Activity-Dependent Postsynaptic Mitochondrial ROS Signaling Drives Avoidance Plasticity in C. elegans.
Theaflavins counteract free fatty acid-driven oxidative-inflammatory injury in endothelial cells through Nrf2-NF-κB axis.
Antioxidants in Menopausal Transition and Male Late-Onset Hypogonadism for the Prevention of Diabetes.
Polyphenols Suppress Intracellular Zinc Deficiency-Induced ROS Production and NLRP3 Inflammasome Activation in Microglial and Neuronal Cells.
Indices of Arterial Stiffness and the Alzheimer's Disease Biomarker, p-tau217, in Non-Demented Midlife Women.
Creatine and cognitive function in rodents: A systematic review of behavioral and neurobiological evidence.
Exploring Glycocalyx shedding markers: A comparative analysis of plasma markers among premenopausal and postmenopausal women.
Saffron and its Bioactive Constituents as Mitochondria-Targeted Protectors Against Organ Injury.
Human sex-specific hormone effects on cerebrovascular health in males and females.
Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.

Oxid Med Cell Longev. 2026 ;2026(1): e8685788

Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.

Kunjal Kiran Pai, Shambhavi Shetye, Rakshith Patil, Shravya Acharya, Kishan S Kulal, Ajeetkumar Patil, Saritha U Kamath.

   BACKGROUND: Nutrition is a key modifiable factor supporting mitochondrial health and is essential for ovarian function and women's health across the life course. From menarche to menopause, mitochondrial efficiency underpins physiological balance. The menopausal transition is particularly critical, as hormonal and neuroendocrine changes are associated with impaired mitochondrial function and increased risk of age-related disorders.
AIM: This review aimed to systematically review and synthesize the available evidence on mitochondrial function across in vitro, animal, and human studies and to evaluate the potential protective role of vitamins and nutrients in maintaining mitochondrial health, with attention to sex-specific findings.
METHODS: A systematic search was conducted across multiple electronic databases. Forty-six eligible studies were identified and critically reviewed for evidence on mitochondrial function, sex-based differences, and nutritional influences.
RESULTS: Mitochondrial dysfunction may contribute to the pathophysiology of age-related disorders, including osteoporosis, cardiovascular disease, neurodegenerative conditions, and cancer. Nutritional factors are crucial for preserving mitochondrial integrity. Vitamins C, E, and D, NAD + precursors such as nicotinamide riboside, coenzyme Q10, MitoQ, fucoxanthin, and cabergoline reduce oxidative stress, enhance mitochondrial biogenesis, support electron transport chain activity and ATP production, and maintain redox balance. These actions promote mitochondrial resilience and cellular energy metabolism. Evidence further indicates that women, particularly during the menopausal transition, exhibit heightened vulnerability to mitochondrial dysfunction, highlighting the relevance of nutrition-based interventions.
CONCLUSION: Optimizing dietary intake of vitamins, antioxidants, and mitochondrial cofactors is a cost-effective, accessible strategy to support mitochondrial health and reduce age-related disease risk in women.

Keywords:  mitochondria; nutrition; vitamins; women’s health

DOI:  https://doi.org/10.1155/omcl/8685788
Hum Mol Genet. 2026 Jun 12. pii: ddag023. [Epub ahead of print]35(12):

Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.

Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter.

  Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.

Keywords:  Congenital myopathy; Mitochondria; NAD+ metabolism; Nemaline myopathy; Skeletal muscle

DOI:  https://doi.org/10.1093/hmg/ddag023
PLoS One. 2026 ;21(6): e0352355

Mitochondrial oxidative stress promotes the accumulation of advanced glycation end products.

Firoz Akhter, Sourav Samanta, Alexandre A Sosunov, Huawei Wu, Ethan Kim Tieu, Shi Fang Yan, Shirley ShiDu Yan.

Advanced glycation end products (AGEs) are a class of toxic metabolites that contribute to disease progression. In our previous study, we demonstrated that age-related AGE accumulation is associated with mitochondrial dysfunction. However, the direct link between mitochondrial dysfunction and AGE accumulation within the context of AD pathogenesis has not yet been fully explored. It also remains unclear whether mitochondrial stress and mitochondrial reactive oxygen species (ROS) drive the accumulation of AGEs. This study, for the first time, provides evidence of progressive AGE accumulation in the cortical mitochondria of AD mice exhibiting mitochondrial dysfunction and Aβ pathology. AGE levels were significantly correlated with Aβ-induced mitochondrial dysfunction, oxidative stress, and amyloid pathology. Notably, mitochondrial stress induced by a mitotoxin significantly increased the accumulation of AGEs in cellular and mitochondrial compartments. Scavenging mitochondrial ROS using the mitochondria-targeted antioxidant reduced AGE accumulation and improved mitochondrial function. Our findings highlight the role of mitochondrial dysfunction in AGE metabolism and provide new insights into the pathogenesis of AD.

DOI: https://doi.org/10.1371/journal.pone.0352355
Biomolecules. 2026 Jun 12. pii: 867. [Epub ahead of print]16(6):

Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.

Evelina Charidemou, Eleni Andreou, Christos Papaneophytou.

  Mitochondrial reactive oxygen species (mtROS) are central regulators of cellular function, yet their biological roles are often reduced to an oxidative-stress/antioxidant dichotomy. This review reframes mtROS through the concept of mitohormesis, in which outcomes are neither inherently harmful nor beneficial but are determined by a defined set of contextual variables. We present a mechanistic framework in which mtROS effects depend on chemical species identity, sub-mitochondrial site of production, temporal dynamics, redox-buffering capacity, and metabolic state; together, these variables determine whether mtROS promote adaptive eustress or pathological distress. We then show that, across polyphenols, isothiocyanates, terpenoids, alkaloids, and quinones, the biologically relevant effects of natural redox-modulating compounds are mediated less by direct radical scavenging than by pro-hormetic mechanisms, including mild electron transport chain perturbation, nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) activation, modulation of mitochondrial membrane potential, mitochondrial quality control, and NAD+/NADPH regulation. Applying this framework to disease reveals strong tissue and state dependence: neurodegeneration favors buffering expansion and mitophagy; metabolic disease may benefit from exercise-mimetic and NRF2-activating strategies; cardiovascular disease illustrates mitohormesis through ischemic preconditioning and CoQ10 supplementation; and cancer requires distinction between prevention and therapy because redox buffering can either protect normal tissue or support tumor survival. Finally, we argue that the failure of non-specific antioxidant supplementation is mechanistically predictable and propose context-aware, biomarker-guided, temporally optimized, and compartment-targeted redox interventions as a more rational translational path.

Keywords:  NRF2/KEAP1 pathway; mitochondria-targeted therapeutics; mitochondrial ROS; mitohormesis; phytochemicals; redox buffering; redox signaling; reverse electron transport

DOI:  https://doi.org/10.3390/biom16060867
bioRxiv. 2026 Jun 10. pii: 2026.06.09.730804. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia C Liu, Catherine Kelly, Ke Bo, Tor D Wager, Eugene V Mosharov, Martin Picard.

Mitochondria support the bioenergetic processes that enable brain function and cognition, but we have lacked a label-free, non-invasive approach to explore how brain mitochondria are linked to ageing, disease, and cognition in humans. A recently introduced MitoBrainMap neuroimaging framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here, we tested whether this framework captures meaningful age- and pathology-related mitochondrial variation. Consistent with existing literature, we find that MR-predicted mitochondrial density and tissue respiratory capacity consistently declined with age, whereas mitochondrial respiratory capacity-an index of mitochondrial quality-was relatively preserved across the lifespan. Moreover, the relations among specific mitochondrial features predicted from our algorithm were consistent with their biological organization, supporting preliminary construct validity for MR-predicted mitochondrial features. In patients with rare mitochondrial diseases, predicted maps revealed region-specific alterations in mitochondrial density and respiratory chain components, particularly the expected compensatory upregulation of complex II, but not of other mitochondrial genome-encoded components. Finally, the MR-based mitochondrial features were associated with the energetic stress marker GDF15 measured in blood, as well as with cognitive performance measures, linking the novel predictions of brain mitochondria to systemic stress and behavior. These findings introduce a first-generation, label-free, neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.64898/2026.06.09.730804
Cells. 2026 Jun 16. pii: 1091. [Epub ahead of print]15(12):

Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.

Mei Ma, Jialin Li, Wentao Pang, Ziyi Zhang, Yong Zhang, Hai Bo.

  Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.

Keywords:  Drp1; ROS; exercise; mitochondrial adaptation; skeletal muscle atrophy

DOI:  https://doi.org/10.3390/cells15121091
Alzheimers Dement (N Y). 2026 Apr-Jun;12(2):12(2): e70278

A combination of ketones and NAD+ precursor preserves white matter integrity in mild cognitive impairment.

Maggie Roy, Mélanie Fortier, Valérie St-Pierre, Marie-Christine Morin, Arnaud Boré, Manon Edde, Camille Vandenberghe, Karine Groulx, Étienne Croteau, Gabriel Richard, Stanislas Thoumyre, Tamas Fulop, Christian Bocti, François Rheault, Bernard Cuenoud, Maxime Descoteaux, Stephen C Cunnane.

   INTRODUCTION: Brain glucose metabolism declines and myelin deteriorates as Alzheimer's disease (AD) develops. Adequate energy supply to white matter (WM) is critical to maintain myelin integrity and axonal function. An exogenous source of ketones bypasses the glucose‑specific brain energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). The BREAK-AD (BRain Energy Activation with Ketones in AD) trial tested a ketone salt and nicotinamide adenine dinucleotide (NAD+) precursor mixture to compensate for reduced brain glucose uptake in MCI.
METHODS: Participants were randomized to a placebo (n = 15) or active supplement (β-hydroxybutyrate salts + nicotinamide riboside (NR); n = 15). Brain ketone and glucose metabolism (quantified by positron emission tomography [PET]), and cognitive performance were assessed before and at the end of the 6-month intervention. For WM analysis, seven tracts of interest were extracted using diffusion magnetic resonance imaging (MRI), and myelin density measures were derived from magnetization transfer (MT) imaging.
RESULTS: Total gray matter ketone uptake increased by 2.4-fold (p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1-3.6-fold across all seven tracts of interest (p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix (p = 0.027), with no change in the active group. Improved processing speed was significantly associated with post-intervention change in myelin density (r = -0.39 to -0.59; p = 0.002-0.046) and ketone uptake (r = -0.40 to -0.52; p = 0.010-0.046) in WM tracts. Ketone uptake in specific WM tracts (fornix, uncinate and arcuate fasciculi), as well as in the composite of all tracts of interest was strongly associated with myelin density.
DISCUSSION: This study shows for the first time that improved myelin density may help explain the positive association between increased WM ketone uptake and improved processing speed in MCI after a ketone salt and NAD+ precursor supplementation.

Keywords:  Alzheimer's disease; FDG; MTR; NAD; PET imaging; beta‐hydroxybutyrate; brain metabolism; diffusion MRI; ketogenic supplement; ketone; mild cognitive impairment; myelin; processing speed; tractography; white matter

DOI:  https://doi.org/10.1002/trc2.70278
Biomolecules. 2026 May 31. pii: 817. [Epub ahead of print]16(6):

Effects of Physical Exercise with and Without Nutritional Supplementation on Serum Albumin in Older People: A Systematic Review and Meta-Analysis.

Pablo Aravena-Sagardia, Edgar Vásquez-Carrasco, Álvaro Levín Catrilao, Mauricio Barramuño-Medina, Jordan Hernandez-Martinez, Cristian Sandoval-Vásquez, Pablo Valdés-Badilla, Bruno Bizzozero-Peroni.

   BACKGROUND: This comprehensive review with meta-analysis was to evaluate the effects of physical exercise interventions alone, as well as in combination with nutritional supplementation, on serum albumin levels in older people.
METHODS: A systematic literature review was performed across eight general electronic databases from inception to March 2026. The risk of bias was evaluated with the RoB 2 tool, and the certainty of evidence was determined using GRADE. The protocol has been registered in PROSPERO with registration number CRD420251072030.
RESULTS: A total of six randomized controlled trials were included, involving 330 older people (mean age: 72.1 ± 5.4 years, 61% female). Physical exercise interventions alone significantly improved serum albumin levels in older people, whereas combined interventions including nutritional supplementation did not show additional significant effects. The majority of the studies assessed were deemed to have a significant risk of bias, resulting in a low overall certainty of evidence.
CONCLUSIONS: Physical exercise treatments elevated blood albumin levels in older people; however, the combination of physical exercise and nutritional supplementation did not have a meaningful effect. Due to the limited reliability of the evidence, more extensive, high-caliber research are required.

Keywords:  aging; biomarkers; exercise therapy; nutritional status; older adults

DOI:  https://doi.org/10.3390/biom16060817
Antioxidants (Basel). 2026 May 29. pii: 689. [Epub ahead of print]15(6):

Ginkgo Biloba Extract Ameliorates Age-Related Mitochondrial Deficits in Human iPSCs and Their Derived Neurons and Astrocytes.

Imane Lejri, Amandine Grimm, Anne Eckert.

  Mitochondrial dysfunction is a central feature of aging, driving bioenergetic decline, increased oxidative stress, and increased vulnerability to neurodegenerative diseases. Human induced pluripotent stem cells (iPSCs) and iPSC-derived neurons provide powerful models to study these processes. Ginkgo biloba extract GBE LI1370 (GBE) has demonstrated antioxidant and mitochondria-protective properties in preclinical models, including improvements in mitochondrial membrane potential, reduction in reactive oxygen species, and enhanced neuronal survival. However, its effects on mitochondrial function in human iPSCs and their differentiated derivatives in the context of aging have not yet been investigated. This study evaluated the mitochondrial protective effects of GBE (100 µg/mL) in an established iPSC-based model of aging and in neurons and astrocytes derived from aged iPSCs. Mitochondrial parameters, including ATP production, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS), superoxide levels, and mitochondrial respiration, were assessed. Aged iPSCs exhibited reduced ATP production and MMP, together with increased mtROS and superoxide levels compared to young controls. Astrocytes derived from aged iPSCs also displayed mitochondrial dysfunction. Treatment with GBE for 24 h increased ATP production and MMP, reduced oxidative stress, and improved mitochondrial respiration in both young and aged iPSCs, as well as in aged iPSC-derived neurons and astrocytes. These preliminary donor-based findings support further investigation of GBE-associated mitochondrial responses in human donor-derived cellular models of aging and warrant validation in larger donor cohorts.

Keywords:  Ginkgo biloba extract; aging; bioenergetics; iPSC-derived astrocytes; iPSC-derived neurons; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3390/antiox15060689
J Physiol Biochem. 2026 Jun 23. pii: 59. [Epub ahead of print]82(1):

The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency.

Mikhail V Dubinin, Konstantin N Belosludtsev.

  Mitochondrial Ca²⁺ dysregulation is a central pathogenic event in skeletal muscle disorders, yet the dichotomy between overload and deficiency is often overlooked. This review summarizes mechanisms governing mitochondrial Ca²⁺ transport and sarcoplasmic reticulum-mitochondria communication. We examine prerequisites of Ca²⁺ overload, including RyR1/SERCA dysfunction and mitochondrial calcium uniporter (MCU) complex remodeling, leading to suppressed ATP synthesis, reactive oxygen species overproduction, and necrosis. Conversely, we address mitochondrial Ca²⁺ deficiency in aging, sarcopenia, and diabetes, resulting from altered MCU stoichiometry and reduced organelle tethering, causing metabolic inflexibility and impaired antioxidant defense. Additionally, therapeutic strategies limiting Ca²⁺ overload and prospects of pharmacological MCU activation to enhance bioenergetics in sarcopenia are discussed.

Keywords:  Calcium signaling; MCU complex; Mitochondrial Ca²⁺ deficiency; Mitochondrial Ca²⁺ overload; Sarcoplasmic reticulum-mitochondria coupling; Skeletal muscle

DOI:  https://doi.org/10.1007/s13105-026-01197-9
Free Radic Biol Med. 2026 Jun 25. pii: S0891-5849(26)00898-1. [Epub ahead of print]

Metabolism of the antioxidant micronutrient ergothioneine as a plasma biomarker of cognitive resilience in older people with Alzheimer's disease amyloid pathology.

Joyce R Chong, Irwin K Cheah, Richard M Tang, Barry Halliwell, Christopher P Chen, Mitchell K P Lai.

   BACKGROUND: Associations between dietary micronutrients and cognitive resilience to Alzheimer's disease (AD) amyloid pathology is currently unknown. We investigated whether plasma levels of L-ergothioneine (ET), its metabolite L-hercynine (HC), and their ratio (HC:ET, as an index of ET metabolism) affect known associations between biomarkers of amyloid pathology (p-Tau181 or p-Tau217) and cognitive decline.
METHODS: 259 initially dementia-free participants recruited from memory clinics and the community in Singapore had baseline measurements of plasma p-Tau, ET, HC, as well as annual neuropsychological assessments for up to 5 years to derive cognitive trajectories based on Clinical Dementia Rating-Sum of Boxes (CDR-SB) slopes.
RESULTS: High HC:ET attenuated the positive correlations between plasma p-Tau and CDR-SB slopes. Compared with participants with low amyloid burden, participants with high amyloid burden had higher risk of cognitive decline when HC:ET was low (Hazard ratio [HR] = 2.33, p = 0.002), but not when HC:ET was high (HR = 1.47, p = 0.32).
CONCLUSION: The identification of ET metabolism as a novel biomarker of cognitive resilience supports further investigations into mechanisms underlying its neuroprotectant properties. ET should be further assessed as a potential candidate for countering amyloid pathology-associated cognitive decline.

Keywords:  Alzheimer’s disease; Antioxidants; Biomarkers; Cognitive resilience; L-Ergothioneine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.043
bioRxiv. 2026 Jun 08. pii: 2026.06.03.729204. [Epub ahead of print]

Why diabetes matters in dementia studies: Excluding diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.

Aakruti Kaikini, Anqi Shi, Paul Francis, Russell Swerdlow, Claire Troakes, Jaimee Kennedy, Alan Hodgkinson, Afshan N Malik.

INTRODUCTION: Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. We hypothesised that AD is associated with reduced mitochondrial DNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.
METHODS: Post-mortem hippocampus, amygdala, and cerebellum samples (N=66-77) from non-cognitively impaired (NCI) and AD donors, with and without diabetes, were analysed. mtDNA-CN was quantified by absolute quantification.
RESULTS: Overall, mtDNA-CN was lower in AD. However, stratification by diabetes revealed opposite changes: non-diabetic AD cases showed reduced mtDNA-CN, whereas diabetic cases showed higher mtDNA-CN across all regions irrespective of cognitive status.
DISCUSSION: These findings confirm multiregional loss of mtDNA-CN in the AD brain, most evident in the absence of diabetes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes can mask effects has important implications for dementia studies.

DOI: https://doi.org/10.64898/2026.06.03.729204
bioRxiv. 2026 Jun 12. pii: 2026.06.05.730457. [Epub ahead of print]

Activity-Dependent Postsynaptic Mitochondrial ROS Signaling Drives Avoidance Plasticity in C. elegans.

Kaz M Knight, Zephyr Lenninger, Ennis Deihl, Rachel L Doser, Frederic J Hoerndli.

Reactive oxygen species (ROS) are signaling molecules involved in neuronal excitatory function, with mitochondrial ROS (mitoROS) playing key roles in metabolic regulation and stress responses. Studies have shown that neuronal activity upregulates mitoROS production through oxidative phosphorylation, but it remains unclear if and how acute elevations in mitoROS influence synaptic plasticity. Here, we develop an avoidance sensitization paradigm in C. elegans using optogenetic excitation and training of nociceptive ASH neurons to initiate avoidance reversals by downstream activation of the AVA command interneurons. Using this paradigm, we show that the probability of reversal to light stimulation increases 4-hours after optogenetic training, indicating behavioral sensitization. This avoidance sensitization is accompanied by an increase of surface glutamate receptor (GLR-1) levels at ASH-AVA synapses which is dependent on postsynaptic expression of GLR-1 and active transcription. Interestingly, we find that somatic and nerve ring mitochondria produce ROS after optogenetic training. We show that this mitochondrial ROS (mitoROS) peak is dependent on postsynaptic GLR-1 and MCU-1 function during optogenetic training and is necessary for avoidance sensitization. Finally, we demonstrate that postsynaptic signaling by mitoROS in AVA is sufficient to induce avoidance sensitization. Postsynaptic photoactivation of mitochondria-targeted Killer Red in AVA, calibrated to produce the mitoROS peak observed during training, induces avoidance sensitization bypassing optogenetic training and MCU-1 requirement. Our results indicate that activity-dependent mitoROS signaling can instruct synaptic strengthening and directly modulate circuit function and behavior.

DOI: https://doi.org/10.64898/2026.06.05.730457
Front Immunol. 2026 ;17 1807168

Theaflavins counteract free fatty acid-driven oxidative-inflammatory injury in endothelial cells through Nrf2-NF-κB axis.

Yufei Zhao, Biao Qu.

   Background: Chronically elevated circulating free fatty acids (FFAs) are key drivers of lipotoxic injury by triggering a self-amplifying oxidative stress-inflammation cascade, thereby contributing to metabolic and cardiovascular diseases. Vascular endothelial dysfunction represents an early and causal event in this process. Although black tea-derived theaflavins (TFs) possess antioxidant and anti-inflammatory properties, the subtype-specific and tissue-parallel effects of TFs against FFA-induced oxidative-inflammatory injury remain incompletely understood.
Methods: FFA-induced lipotoxicity models were established in vascular endothelial cells and hepatocytes to systematically compare the protective effects of four major TF subtypes: theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B), and theaflavin-3, 3'-digallate (TFDG). Antioxidant capacity was assessed using both cell-free systems and oxidant-stimulated cellular models. Mechanistic studies were conducted to determine the involvement of the Nrf2-NF-κB axis.
Results: All TF subtypes significantly attenuated FFA-induced ROS overproduction, lipid peroxidation, and inflammatory mediator release in both endothelial cells and hepatocytes, whereas no major changes in intracellular lipid accumulation were observed. Among the four subtypes, TF1 consistently exhibited the strongest and most reproducible cytoprotective effects. Further analyses demonstrated that TFs, particularly TF1, restored cellular redox homeostasis not only through direct free radical scavenging but, more importantly, through activation of endogenous antioxidant defenses. Transcriptomic and bioinformatics analyses indicated that TF1 enhanced antioxidant-related gene expression while suppressing inflammatory genes, with enrichment of oxidative stress-, atherosclerosis-, and NF-κB-related pathways and Nrf2 appearing as a key node. Molecular docking predicted a favorable TF1-Keap1 interaction. Consistently, TF1 promoted Nrf2 nuclear translocation and HO-1 expression, restored SOD2 and GPX1 expression, reduced mitochondrial ROS, and attenuated IκBα phosphorylation and NF-κB p65 nuclear accumulation. Silencing Nrf2 markedly weakened these protective effects, supporting an important role of Nrf2 in TF1-mediated endothelial protection.
Conclusion: TFs act as natural modulators of FFA-driven oxidative-inflammatory injury, with TF1 emerging as the most potent subtype. TF1 protects against FFA-induced endothelial dysfunction partly through an Nrf2-associated mechanism involving enhanced antioxidant responses and attenuation of NF-κB-related inflammatory signaling.

Keywords:  Nrf2-NF-κB axis; endothelial injury; inflammatory response; lipotoxicity; oxidative stress; theaflavins; vascular endothelial cells

DOI:  https://doi.org/10.3389/fimmu.2026.1807168
Antioxidants (Basel). 2026 May 24. pii: 659. [Epub ahead of print]15(6):

Antioxidants in Menopausal Transition and Male Late-Onset Hypogonadism for the Prevention of Diabetes.

Maria Karaflou, Athina Kaprara, Dimitrios G Goulis.

  In the modern day, despite advances in medicine and the prolongation of life expectancy, the age of menopause and male late-onset hypogonadism remains the same. This narrative review describes the physiology of the human reproductive system in females and males based on clinical and experimental studies. It explores the impact of gonadal aging and reproductive hormone withdrawal on the development of insulin resistance and diabetes and summarizes the use of antioxidants for the prevention of diabetes during menopausal transition and male late-onset hypogonadism. Maintaining high antioxidant capacity in these periods prevents the metabolic consequences of oxidative stress and improves health span trajectories. In clinical practice, we conclude that antioxidants should be used with caution to avoid the 'antioxidant paradox'.

Keywords:  antioxidants; diabetes prevention; late-onset hypogonadism; menopause; transition

DOI:  https://doi.org/10.3390/antiox15060659
Biomolecules. 2026 Jun 21. pii: 920. [Epub ahead of print]16(6):

Polyphenols Suppress Intracellular Zinc Deficiency-Induced ROS Production and NLRP3 Inflammasome Activation in Microglial and Neuronal Cells.

Ayumi Matsushita, Maki Kimura, Naoko Tajima, Tsuyoshi Yamanaka, Masato Inazu.

  Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives-chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)-exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1-42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3-42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer's disease.

Keywords:  Alzheimer’s disease; NLRP3 inflammasome; microglia; neuroinflammation; oxidative stress; polyphenols; reactive oxygen species; zinc deficiency

DOI:  https://doi.org/10.3390/biom16060920
Pulse (Basel). 2026 Jan-Dec;14(1):14(1): 78-92

Indices of Arterial Stiffness and the Alzheimer's Disease Biomarker, p-tau217, in Non-Demented Midlife Women.

Benecia Wan Qing Thia, Darren Yuen Zhang Tan, Beverly Wen Xin Wong, Liang Shen, Lingli Gong, Lieng-Hsi Ling, Christopher Li-Hsian Chen, Eu-Leong Yong.

   Introduction: The association between indices of arterial stiffness and/or pressure wave reflection with Alzheimer disease amyloid-β accumulation and tau pathology in the brain is unclear. Deficiency of estrogen post-menopause may be an important contributor to changes in these indices to affect Alzheimer's disease progression. We aimed to assess the associations between indices of arterial stiffness and/or pressure wave reflection and the Alzheimer's disease blood biomarker, p-tau217, in midlife women without dementia.
Methods: This cross-sectional analysis of participants from the Integrated Women's Health Program (IWHP) enrolled community-dwelling midlife women without dementia attending routine health screening at the National University Hospital in Singapore. Fasted blood p-tau217 was measured using the Simoa® ALZpath p-tau217 Advantage PLUS (Quanterix, MA, USA). Aortic augmentation index (AIx) and reflection index (RI) were obtained from peripheral arterial pressure waveforms and cardio-ankle vascular index (CAVI) measured using pressure cuffs on the extremities and a phonocardiogram. Multivariable linear regression was used to examine the independent associations between indices of arterial stiffness and serum levels of p-tau217.
Results: Among 871 participants (mean age: 62.80 ± 6.02 years), every SD increase in AIx and RI scores was both associated with 0.010 pg/mL (95% CI: 0.003-0.017, p = 0.004) higher blood p-tau217 levels after adjustment for age, employment status, BMI, mild cognitive impairment, hypertension, cholesterol-HDL ratio, renal function, and ApoE4 carrier status. With natural logarithmic transformed p-tau217, RI remained significantly associated with ln(p-tau217), β = 0.026 (0.007, 0.045), p = 0.007, after covariate adjustment. For AIx, the association was attenuated but remained directionally consistent. Trends for the association between CAVI and blood p-tau217 level were not statistically significant after adjustment for covariates.
Conclusion: Increases in indices of arterial stiffness and pressure wave reflection were associated with higher blood p-tau217 levels in community-dwelling midlife women without dementia. These indices may be markers of risk for tau-related pathologies in the brain.

Keywords:  Alzheimer’s disease; Augmentation index; Cardio-ankle vascular index; Community-dwelling women; Indices of arterial stiffness; Menopause; Pressure wave reflection; Reflection index; p-tau217

DOI:  https://doi.org/10.1159/000552328
Behav Brain Res. 2026 Jun 22. pii: S0166-4328(26)00316-5. [Epub ahead of print]513 116340

Creatine and cognitive function in rodents: A systematic review of behavioral and neurobiological evidence.

Saúl Sal-Sarria, Andrea Fernández-Blanco.

  Creatine monohydrate is one of the most widely used dietary supplements worldwide, and growing preclinical evidence suggests it may exert cognitive benefits beyond its established role in energy metabolism. However, the conditions under which these effects emerge, and the neurobiological mechanisms mediating them, remain incompletely characterised. A systematic review was conducted following PRISMA 2020 guidelines, searching Scopus, PubMed, and Web of Science for experimental studies published between 2015 and 2026. Studies were eligible if they evaluated the effects of creatine supplementation on cognitive performance in rodent models and reported behavioural and/or neurobiological outcomes. Risk of bias was assessed using SYRCLE's tool for animal studies. Nineteen studies were included, comprising experiments rodents across healthy animals and models of neurodegeneration, metabolic insult, perinatal stress, and creatine biosynthesis deficiency. Creatine improved learning and memory in the majority of studies. The magnitude of cognitive benefits was moderated by route of administration, with intranasal delivery showing superior brain uptake and cognitive effects relative to oral supplementation, treatment duration, and sex. Mechanistically, cognitive improvements were associated with enhanced mitochondrial respiratory capacity, upregulation of synaptic plasticity proteins (CaMKII, PSD-95, BDNF) via CaMKII/CREB and PI3K/AKT/mTOR signalling, attenuation of neuroinflammation through NF-κB suppression and STAT1 inhibition, and reduction of oxidative stress through CK-BB restoration. Preclinical evidence consistently supports a cognitive-enhancing role for creatine, mediated by a convergent set of energetic, synaptic, anti-inflammatory, and antioxidant mechanisms. Translating these findings to clinical applications will require brain-targeted delivery strategies, systematic consideration of sex as a biological variable, and mechanistically rigorous study designs.

Keywords:  Cognition; Creatine; Memory; Neuroprotection; Rodents; Supplementation

DOI:  https://doi.org/10.1016/j.bbr.2026.116340
Physiol Rep. 2026 Jun;14(12): e70964

Exploring Glycocalyx shedding markers: A comparative analysis of plasma markers among premenopausal and postmenopausal women.

Mounica Ayyalasomayajula, David N Proctor, Janhavi J Damani, Christine Bowlus, Jigar Gosalia, Jocelyn M Spicuzza.

  The endothelial glycocalyx (eGC) is a protein-rich, hairlike structure covering the luminal surface of endothelial cells, vital for vascular health. Aging and cardiovascular disease (CVD) can compromise eGC integrity, potentially preceding conventional indicators of vascular dysfunction such as reduced endothelium-dependent vasodilation and increased arterial stiffness. SDC-1 and HS are key glycosaminoglycans and validated plasma biomarkers reflecting glycocalyx integrity. During menopause the decline in estrogen, a vascular-protective hormone, has been linked to increased glycocalyx degradation and decreased nitric oxide (NO) synthesis contributing to endothelial dysfunction. This study examined glycocalyx degradation in premenopausal females versus postmenopausal females (early and late stages). Resting plasma samples from premenopausal (n = 11), early-postmenopausal (n = 12) and late-postmenopausal women (n = 13) were analyzed via ELISA for SDC-1 and HS. Late postmenopausal females had significantly higher mean plasma HS concentrations compared to early postmenopausal and premenopausal groups (4049.9 ± 1595.4 vs. 3919.0 ± 999.2, 2986.4 ± 1493.7 ng/mL, p = 0.003). Conversely, SDC-1 levels were higher in premenopausal women (p = 0.036). No correlations were observed between these biomarkers and flow-mediated dilation (all, p > 0.05). Overall, results suggest eGC integrity varies across reproductive stages, emphasizing the need for further research into mechanisms and interventions to preserve vascular health in aging females.

Keywords:  HS; Sydecan‐1; endothelial glycocalyx; menopause

DOI:  https://doi.org/10.14814/phy2.70964
Mol Neurobiol. 2026 Jun 26. pii: 729. [Epub ahead of print]63(1):

Saffron and its Bioactive Constituents as Mitochondria-Targeted Protectors Against Organ Injury.

Fatemeh Pedramfar, Ali Abolhosseini, Cosimo D'Aiello, Vahid Pourbarkhordar, Sohrab Rahmani.

  Mitochondria are central regulators of cellular homeostasis, controlling energy production, redox balance, and programmed cell death. Their dysfunction is a major contributor to oxidative stress, inflammation, and organ injury across a wide spectrum of diseases. Natural products with multi-targeted properties have gained increasing attention as mitochondria-protective agents. Among them, saffron (Crocus sativus L.) and its principal constituents crocin, crocetin, safranal, and the synthetic derivative trans-sodium crocinate (TSC) exhibit potent antioxidant, anti-inflammatory, and cytoprotective activities. Evidence from in vitro and in vivo studies indicates that these compounds reduce reactive oxygen species (ROS) generation, stabilize mitochondrial membrane potential (MMP), and modulate cell death pathways, including the intrinsic mitochondrial pathway and parthanatos. They also enhance mitochondrial biogenesis and dynamics via mechanisms involving Drp1/Fis1, MFN, SIRT3, PGC-1α, and related signaling cascades. Overall, current experimental evidence suggests that saffron and its derivatives may represent promising adjunctive candidates for the prevention and mitigation of organ injury associated with mitochondrial dysfunction. However, further clinical studies are required to validate their therapeutic efficacy and safety in human subjects.

Keywords:  Apoptosis; Mitochondria; Natural products; Organ injury; Oxidative stress; Saffron

DOI:  https://doi.org/10.1007/s12035-026-06016-2
Mech Ageing Dev. 2026 Jun 26. pii: S0047-6374(26)00068-0. [Epub ahead of print] 112216

Human sex-specific hormone effects on cerebrovascular health in males and females.

Brittany Intzandt, Zacharie Potvin-Jutras, Claudine J Gauthier.

  Circulating sex hormone levels decrease in aging, influencing cerebrovascular health. Estradiol has been shown to support female vascular and brain health, though its effects across the menopausal transition remain unknown. Similarly, the influence of testosterone and other hormones in females is not clear. In males, testosterone is associated with positive health outcomes, but the effects of estradiol and other hormones are undetermined. Here, 187 females were categorized as premenopausal, perimenopausal or postmenopausal and 154 males as younger [<50 years] or older [50-70 years]. Magnetic resonance imaging quantified cerebral blood flow (CBF), arterial transit time (ATT), relative cerebrovascular reactivity (CVR) and a blood draw for circulating sex hormones. In females, estradiol was associated with lower ATT during perimenopause. Testosterone exhibited a U-shaped relationship with CVR in premenopausal females, yet was linked to lower CBF and CVR, and longer ATT in postmenopausal females. In males, higher testosterone was correlated with greater CBF in younger participants, while higher estradiol and follicle-stimulating hormone were associated with lower CBF in older males. These findings highlight life stage- and sex-specific associations with between hormones and cerebrovascular markers, emphasizing the potential for hormone-targeted, age and stage-specific interventions to support cerebrovascular health.

Keywords:  arterial transit time; cerebral blood flow; cerebrovascular reactivity; sex hormones

DOI:  https://doi.org/10.1016/j.mad.2026.112216
Cell Commun Signal. 2026 Jun 22.

Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.

Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.

  Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.

Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA

DOI:  https://doi.org/10.1186/s12964-026-03013-9