bims-mistre 2026-05-03 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–05–03
twenty papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial-nuclear crosstalk: A central axis in Alzheimer's disease.
Circulating Growth Differentiation Factor-15 (GDF-15) levels in depressive disorders - A systematic review and meta-analysis of the association between GDF-15 and depression in adult populations.
Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.
Do menopausal symptoms signal early biological aging? Mitochondrial, endocrine and clinical insights.
The Estrogen-Mitochondria Axis in Bipolar Disorder: From Fluctuating Hormones to Failing Bioenergetics.
Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.
From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.
From mice to muscle: does MitoQ translate to human strength in ageing?
The ERβ Agonist, OSU-ERβ-012, Mitigates Inflammation in a Chimeric Model of Systemic Lupus Erythematosus.
The Mitochondrial-Autophagy Axis in MASLD: Mechanisms, Crosstalk, and Therapeutic Targets.
Melatonin and Coenzyme Q10 mitigate Senescence in Human Adipose-Derived Mesenchymal Stem Cells by Restoring Mitophagy and Mitochondrial Proteostasis.
Mechanistic insights into natural product-driven modulation of NLRP3-inflammasome signalling in metabolic syndrome.
Elevation of Mitochondrial Ca2+ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse Soleus Muscle.
The effect of exogenous ketone bodies on cognition across health and disease: a systematic review and meta-analysis.
The impact of dietary phosphorus supplementation on postprandial metabolic outcomes: a systematic review.
Nicotinamide Riboside (NR) Supplementation Exerts Neuroprotective Effects in db/db Mouse Model of Type 2 Diabetes.
NAD+‒circadian rhythm coupling in dementia.
Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.
The Drp1-CoQ10-Coa6-ETC axis represents a therapeutic potential for working memory impairment caused by neuronal mitochondrial dysfunction.
Astragaloside IV delays vascular aging by enhancing mitochondrial fatty acid β-oxidation via the MLXIPL-PPARα/PGC-1α axis.

Ageing Res Rev. 2026 Apr 25. pii: S1568-1637(26)00142-X. [Epub ahead of print] 103150

Mitochondrial-nuclear crosstalk: A central axis in Alzheimer's disease.

Kunal Samantaray, Anupriya Sinha, Dhanendra Tomar, Pooja Jadiya.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and survival pathways, making it a critical determinant of brain aging and AD vulnerability. Despite its importance, the mechanisms coordinating this bidirectional dialogue and how their breakdown drives neurodegeneration remain poorly understood. This review highlights the major molecular pathways governing mito-nuclear signaling under physiological conditions, including anterograde pathways (PGC-1α/NRF1/2/TFAM) and retrograde stress responses (ROS, calcium, mitokines, and the mitochondrial unfolded protein response). In AD, these pathways are disrupted, leading to mitochondrial dysfunction, impaired proteostasis, metabolic reprogramming, and inflammation. Emerging evidence suggests that mito‑nuclear signaling deficits arise early often preceding classical Aβ and tau pathology positioning them as potential upstream drivers of disease. We further discuss therapeutic strategies aimed at restoring mito‑nuclear communication, including NAD⁺ supplementation, mitophagy enhancers, mitochondria‑targeted antioxidants, and gene‑based approaches, emphasizing the importance of combinatorial and cell‑type‑specific interventions. Finally, we highlight how single‑cell and spatial transcriptomic technologies are enabling high‑resolution mapping of mito‑nuclear dynamics in aging and AD. Together, these insights underscore mito‑nuclear signaling as a promising but underexplored therapeutic target for modifying AD progression.

Keywords:  Alzheimer’s disease; aging; bioenergetics; mito-nuclear crosstalk; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1016/j.arr.2026.103150
J Affect Disord. 2026 Apr 26. pii: S0165-0327(26)00688-9. [Epub ahead of print]408 121837

Circulating Growth Differentiation Factor-15 (GDF-15) levels in depressive disorders - A systematic review and meta-analysis of the association between GDF-15 and depression in adult populations.

Aidan Jones-Murphy, Ena Liew, Anuradha Baminiwatta, Serena Griffin, Michael Berk, Breno S Diniz, Malcolm Forbes.

   BACKGROUND: Growth Differentiation Factor-15 (GDF-15) has been proposed as a biomarker of inflammation and cellular stress, both of which are implicated in the pathophysiology of depression. We conducted a systematic review and meta-analysis to evaluate the association between circulating GDF-15 levels and depression.
METHODS: Observational studies assessing GDF-15 levels in adults with depression were included. Eligible studies reported GDF-15 levels measured in blood and used standardized diagnostic criteria for depression. Study quality was assessed using the Newcastle-Ottawa Scale. A meta-analysis was performed on a subset of studies with available data.
RESULTS: Thirteen studies with a total of 55,985 participants were included, of whom 4997 had depression. Study populations included late-life, post-stroke, male-only, and general adult cohorts. Most studies (n = 12) found elevated GDF-15 levels in individuals with depression. Six studies were included in the meta-analysis (n = 5657), which revealed significantly higher GDF-15 levels in depressed individuals compared to controls (standardized mean difference [SMD] = 0.39, 95% CI: 0.19 to 0.58; p = 0.0039). Heterogeneity was moderate to high (I2 = 68.7%) but reduced substantially upon exclusion of one study. Correlations between GDF-15 and depression severity were inconsistent across studies.
CONCLUSIONS: Circulating GDF-15 levels are moderately but significantly elevated in individuals with depression, supporting its role as a potential inflammatory biomarker of depression. However, variability in measurement methods, study populations, and depression assessments limits generalizability. Further longitudinal and mechanistic studies are needed to clarify the clinical utility of GDF-15 in depression diagnosis and prognosis.

Keywords:  Affective disorders; Cytokines; GDF-15; Growth Differentiation Factor-15; MDD; Major depressive disorder

DOI:  https://doi.org/10.1016/j.jad.2026.121837
Mol Biol Rep. 2026 Apr 25. pii: 662. [Epub ahead of print]53(1):

Mitochondrial dysfunction-driven inflammation and β-Cell apoptosis in type 2 diabetes mellitus: mechanistic insights and therapeutic implications.

Satyam Yadav, Gautam Kumar, Sumit Kumar, Khadga Raj Aran, Sourabh Kosey.

  Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic syndrome characterized by chronic hyperglycemia, progressive pancreatic β-cell malfunction, and peripheral insulin resistance. There is growing evidence suggesting that mitochondrial dysfunction and apoptosis play a critical role in the development and advancement of T2DM. Mitochondria are essential for cellular energy metabolism and redox homeostasis. It is the metabolic stress and apoptotic cell death in insulin-producing β-cells and insulin-sensitive tissues induced by mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) production, imbalanced mitochondrial dynamics, impaired mitophagy, mitochondrial fission-fusion imbalance, and defective biogenesis. This review summarizes the molecular pathways by which mitochondrial dysfunction triggers inflammatory responses, such as activation of NLRP3 inflammasomes, cytokine release, and mitochondria-mediated intrinsic apoptotic signaling. We describe the role of these pathways in insulin resistance and in the emergence of diabetic complications like neuropathy, nephropathy, myopathy, and hepatopathy. New treatment approaches aimed at mitochondrial integrity and apoptotic signaling are promising. These are AMPK/PGC-1α pathway activators, mitochondria-targeted antioxidants (MitoQ, SS-31), and mitophagy and ferroptosis modulators. But poor tissue specificity, poor bioavailability, and patient-to-patient variability are limitations in clinical translation. Lastly, the review highlights the possibilities of personalized medicine strategies that incorporate the use of mitochondrial profiling to maximize therapeutic outcomes. Collectively, available evidence suggests that therapeutic strategies restoring mitochondrial quality control in β-cells may offer greater disease-modifying potential than glucose-centric interventions alone.

Keywords:  Apoptosis; Mitochondrial Dysfunction; Oxidative Stress; Type 2 Diabetes Mellitus; β-cell Failure

DOI:  https://doi.org/10.1007/s11033-026-11851-6
Climacteric. 2026 May 01. 1-6

Do menopausal symptoms signal early biological aging? Mitochondrial, endocrine and clinical insights.

Juan E Blümel, Peter Chedraui, María S Vallejo.

  The menopausal transition represents a pivotal period in female aging, marked by profound endocrine, metabolic and cellular shifts. Increasing evidence indicates that menopausal symptoms - vasomotor instability, sleep disturbances, fatigue and cognitive complaints - are more than consequences of estrogen withdrawal, and may serve as a potential clinical indicator of biological aging. Experimental and clinical data suggest that declining estrogen signaling contributes to mitochondrial dysfunction, inflammation and telomere attrition, processes that are closely linked to cellular senescence and tissue deterioration. In addition to estrogen decline, the menopausal transition involves broader endocrine changes. Rising follicle stimulating hormone (FSH) levels, alteration in androgen balance and cortisol dysregulation of the hypothalamic-pituitary-adrenal axis may influence metabolic regulation, musculoskeletal health, stress physiology and body composition. Through these mechanisms, menopausal hormonal changes may contribute to increased cardiometabolic, musculoskeletal and neurocognitive vulnerability in midlife women. Clinical observations increasingly show that severe menopausal symptoms are associated with adverse cardiometabolic profiles, vascular dysfunction and markers of accelerated biological aging. Sleep disturbances and fatigue may further exacerbate metabolic dysregulation and systemic vulnerability, while cognitive complaints may reflect neuroinflammatory and vascular processes associated with aging. By restoring estrogen signaling, menopausal hormone therapy alleviates menopausal symptoms and may influence biological pathways involved in aging. Whether these effects translate into a modification of the aging trajectory remains unclear.

Keywords:  Menopause; biological aging; follicle stimulating hormone; menopause hormone therapy; mitochondrial dysfunction; neuroinflammation; sarcopenia

DOI:  https://doi.org/10.1080/13697137.2026.2663898
Biol Psychiatry Glob Open Sci. 2026 Jul;6(4): 100723

The Estrogen-Mitochondria Axis in Bipolar Disorder: From Fluctuating Hormones to Failing Bioenergetics.

Kassandra A Zachos, Kiana Behravan, Jude Demyati, Ana C Andreazza.

  Bipolar disorder (BD) is a psychiatric illness marked by fluctuating mood states and substantial systemic consequences, including dysregulated bioenergetics, immune modulations, and significant metabolic dysfunction. Although BD affects males and females at comparable rates, the literature indicates that the symptomatology and course of the disorder can differ between sexes. Females with BD are more likely to exhibit rapid cycling and depressive symptoms, whereas in males BD is more frequently associated with reckless behavior and hallucinations. A plausible mechanism for these symptomatology differences may be marked by the estrogen-mitochondria axis, which reflects the bioenergetic consequences of fluctuating estrogen levels on mitochondrial biogenesis (MB). Estrogen constitutes a family of steroid hormones that have critical regulatory roles in many physiological processes, including reproduction, metabolism, and immune regulation. In the context of bioenergetics, estrogen supports mitochondrial function in neural tissue by promoting oxidative phosphorylation, reducing oxidative stress, and regulating MB. In this literature review, we examine evidence linking estrogen fluctuation to periods of psychiatric vulnerability across the life span in females with BD. There is a particular focus on the mechanistic role of estrogen modulating MB, the existing experimental and preclinical evidence underlying this mechanism, and the evaluation of current pharmacological and nutraceutical therapeutics that have the potential to modulate this axis. Finally, we discuss the clinical and future therapeutic implications for behavioral symptomatology across the life span of females with BD. While this review focuses solely on literature on BD, the plausibility of investigating this mechanism extends to other mood disorders and psychiatric diseases.

Keywords:  Bipolar disorder; Estrogen; Hormones; Mitochondria; Mitochondrial biogenesis; Psychiatry

DOI:  https://doi.org/10.1016/j.bpsgos.2026.100723
Front Aging Neurosci. 2026 ;18 1710075

Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.

Ulrik N Mjaaseth, Ming-Fo Hsu, Joseph Arballo, Fawaz G Haj, Viharkumar Patel.

   Introduction: Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired glucose metabolism. While most studies focus on heavily affected brain regions such as the hippocampus and prefrontal cortex, the visual cortex remains relatively preserved in early AD and provides an opportunity to examine metabolic alterations that precede widespread pathology.
Methods: Postmortem human visual cortex samples were obtained from control, mild cognitive impairment (MCI), and AD subjects without non-AD neuropathologic conditions. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry, and expression of key metabolic, inflammatory, and AD-related genes was measured by quantitative PCR. Data analysis was conducted using MetaboAnalyst and R.
Results: Metabolomic profiling revealed progressive disruptions in glucose metabolism, and mitochondrial function across MCI and AD subjects. Gene expression analyses showed reduced levels of glycolytic enzymes (HK1, PFKM, PKM1), mitochondrial regulators (PDHA1, NDUFC1), and the neuronal glucose transporter SLC2A3. Insulin signaling was altered, with decreased IDE and increased INSR and PTPN1 gene expression. Inflammatory markers including TNF, IL1B, and GFAP were elevated in AD. Sex-stratified analyses revealed both shared and distinct metabolic signatures, particularly within glucose and mitochondrial pathways. Several metabolic gene changes correlated negatively with Braak stage, highlighting a progressive decline in energy metabolism alongside tau pathology.
Discussion: These findings demonstrate early and progressive metabolic dysfunction in the visual cortex of MCI and AD subjects. Even in a region with limited structural pathology, profound alterations in energy metabolism were observed, underscoring its central role in AD pathogenesis and highlighting improving neuronal metabolic function as a promising target for therapeutic intervention.

Keywords:  Alzheimer’s disease; Braak staging; glucose metabolism; insulin signaling; mild cognitive impairment; mitochondrial function; neurodegeneration; visual cortex

DOI:  https://doi.org/10.3389/fnagi.2026.1710075
Cells. 2026 Apr 10. pii: 672. [Epub ahead of print]15(8):

From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.

Romina María Uranga, Shailaja Kesaraju Allani.

  The increasing prevalence of obesity and Alzheimer's disease (AD) in the aging population underscores an urgent need to understand the common cellular and metabolic mechanisms they share. Accumulated evidence suggests that overlapping metabolic disturbances contribute to the pathogenesis of these two conditions. In this review, we highlight key underlying interconnecting metabolic pathways: (1) adipose-brain crosstalk mediated by adipokines and adipose tissue-derived extracellular vesicles that can modulate neuronal function and amyloid pathology, (2) dysregulated lipid metabolism affecting cholesterol, sphingolipids, and phospholipids and thereby promoting inflammation, amyloid precursor protein processing, and tau hyperphosphorylation, (3) impaired glycolysis and insulin resistance, which accelerate both obesity and neurodegenerative processes, (4) mitochondrial dysfunction marked by disrupted tricarboxylic acid cycle enzymes and electron transport chain complexes, leading to elevated reactive oxygen species and driving both obesity and AD pathology, and (5) gut microbiota dysbiosis, which can trigger inflammation as well as amyloid and tau aggregation. Together, these mechanisms show that metabolic alterations appear early, preceding clinical disease, and that understanding these underlying connections can provide strategies to protect metabolic health and prevent disease progression.

Keywords:  Alzheimer’s disease; TCA cycle; adipokines; adipose tissue; electron transport chain; glycolysis; gut–brain axis; insulin resistance; lipids; microbiota; mitochondrial dysfunction; obesity

DOI:  https://doi.org/10.3390/cells15080672
J Physiol. 2026 Apr 27.

From mice to muscle: does MitoQ translate to human strength in ageing?

Emilie Y Daroga, Kate A Dunsmore, Tina Y Chen.



Keywords:  MitoQ; ageing; mitochondria; mitoquinone mesylate; reactive oxidative species; skeletal muscle

DOI:  https://doi.org/10.1113/JP291266
ACR Open Rheumatol. 2026 May;8(5): e90031

The ERβ Agonist, OSU-ERβ-012, Mitigates Inflammation in a Chimeric Model of Systemic Lupus Erythematosus.

Braden Zeno, Shane Bruckner, Hongyu Yuan, Morgan Stahl, Timothy Alexandrov, Kyle Jablonski, Judith Lin, Nicholas A Young, Wael N Jarjour.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ damage, affecting women between the ages of 15 and 45 years at a 9:1 rate as compared to men. The etiology of SLE is complex and elusive; however, the susceptibility of women during the years in which estrogen levels are at their highest suggests a significant contribution to the development of SLE. Previously, our group and others have shown that estrogen receptor α (ERα) carrying immune cells are mediators of the proinflammatory effects of estrogen as compared to cells that lack this receptor. ERβ, the other estrogen responsive transcription factor, has been postulated to have an antagonistic effect to ERα, which mediates the anti-inflammatory effects of estrogen.
METHODS: In the pursuit of a drug that is tailored to have a favorable selective estrogenic effect, The Ohio State University Drug Development Institute discovered a novel carborane-based selective ER modulator, OSU-ERβ-012. This ERβ agonist exhibits potent binding of human ERβ (Ki = 2.0 nM) and functional selectivity for ERβ over ERα of at least 200-fold. We tested the effectiveness of OSU-ERβ-012 in treating lupus-humanized NSG mice by examining serum for the presence of inflammatory cytokines and histopathology of hearts and kidneys.
RESULTS: The humanized mice exhibited increased expression of inflammatory cytokines, pericarditis, and increased glomerular size, which were all mitigated by the treatment with OSU-ERβ-012.
CONCLUSION: OSU-ERβ-012 is an effective therapeutic in this NSG mouse model with humanized SLE because it inhibits the proinflammatory renal and cardiac phenotype.

DOI: https://doi.org/10.1002/acr2.90031
Compr Physiol. 2026 Jun;16(3): e70155

The Mitochondrial-Autophagy Axis in MASLD: Mechanisms, Crosstalk, and Therapeutic Targets.

Gaurab Bhaduri, Anchin Kalia, Banshi Saboo, Sanjay Bandyopadhyay.

   BACKGROUND: This review seeks to integrate contemporary evidence regarding mitochondrial dysfunction and autophagic regulation in metabolic dysfunction associated steatotic liver disease (MASLD), elucidating mechanistic pathways, indigenous determinants, and emerging therapeutic targets.
METHODS: A thorough search was performed in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar. Research publications on mitochondrial activity, oxidative phosphorylation, fatty acid oxidation, mitophagy, lipophagy, and associated autophagic pathways in MASLD or MASH were incorporated.
RESULTS: This review integrates findings that show mitochondrial dysfunction is a key mediator of MASLD progression. Mitochondrial dysfunction due to fatty acid oxidation, electron transport chain uncoupling, increased reactive oxygen species, and was found to be associated with steatosis, inflammation, and fibrosis. Simultaneous inhibition of autophagy, including lipophagy and mitophagy, contributes to lipid accumulation and persistence of dysfunctional mitochondria. Novel mediators of MASLD progression include gut dysbiosis, ferroptosis, and mitoDAMP signaling.
CONCLUSION: In summary, the results indicate that mitochondrial dysfunction and autophagy dysregulation are interdependent mediators of MASLD pathogenesis. Their interaction mediates metabolic overload to oxidative stress, inflammation, and fibrotic remodeling. The understanding of these mechanisms provides a common platform for MASLD progression and suggests mitochondrial quality control, autophagy modulation, and associated metabolic pathways as promising targets for future MASLD therapeutic and preventive strategies.

Keywords:  autophagy; lipotoxicity; liver fibrosis; metabolic dysfunction–associated steatotic liver disease (MASLD); mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1002/cph4.70155
PLoS One. 2026 ;21(4): e0347781

Melatonin and Coenzyme Q10 mitigate Senescence in Human Adipose-Derived Mesenchymal Stem Cells by Restoring Mitophagy and Mitochondrial Proteostasis.

Aleena Vikraman, Logeswari Ravi, Naveena Kandasamy, Anuradha Dhanasekaran.

Mitochondrial quality control is a crucial factor governing self-renewal capacity, maintenance of metabolic balance, and cellular longevity in stem cells. Impaired mitophagy significantly contributes to cellular senescence, causing accumulation of damaged mitochondria and impaired proliferative capacity of cells, leading to reduced therapeutic efficiency. This study explores mitophagy's role in regulating senescence in human adipose-derived mesenchymal stem cells (HADMSCs) and evaluates the therapeutic potentiality of antioxidants-melatonin and coenzyme Q10 (CoQ10) targeting mitochondria. It also examines the impact of antioxidant intervention aimed at improving the fate and survival, thereby establishing a connection between metabolic reprogramming and mitophagy. Our study found that stress-induced HADMSCs have reduced Mitochondrial Membrane potential (MMP), increased ROS, and increased senescence-associated β-galactosidase activity as observed through fluorescence-based imaging and biochemical assays. It was observed that antioxidant intervention has prevented the damage caused by the stress and reduced mitochondrial ROS and lipid peroxidation and has significantly restored mitophagy markers like Parkin, NDP52, BNIP3, BNIP3L/Nix, and LC3B. Our findings suggest that antioxidants induced pharmacological stimulation of mitophagy could potentially reverse stem cell aging and prevent functional decline, thereby improving regeneration and offering new insights and perspectives on mitochondrial health for improved efficiency of stem cell transplantation, maintenance and longevity of HADMSCs.

DOI: https://doi.org/10.1371/journal.pone.0347781
Inflamm Res. 2026 Apr 28. pii: 100. [Epub ahead of print]75(1):

Mechanistic insights into natural product-driven modulation of NLRP3-inflammasome signalling in metabolic syndrome.

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

   INTRODUCTION: Metabolic syndrome (MetS) comprises a cluster of interrelated metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia and hypertension, mainly driven by chronic low-grade inflammation. Among innate immune pathways, the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical molecular link between metabolic stress and inflammatory signalling, promoting caspase-1 activation, interleukin (IL)-1β/IL-18 maturation and pyroptosis across metabolically active organs such as adipose tissue, liver and pancreas. Persistent NLRP3 activation, triggered by mitochondrial dysfunction, oxidative stress, ionic imbalance and impaired autophagy, contributes directly to insulin resistance, hepatic steatosis, β-cell dysfunction and cardiometabolic complications, highlighting natural products as promising multi-target modulators capable of attenuating NLRP3-driven metabolic inflammation.
METHODS: The literature search was conducted in PubMed and Scopus to identify recent studies investigating phytochemical-mediated modulation of NLRP3 inflammasome signalling in MetS from 2020 to December 2025. Eligible studies were screened for mechanistic relevance, with particular emphasis on NLRP3-centred pathways.
RESULTS AND CONCLUSION: The consolidated evidence demonstrates that diverse classes of natural products, including flavonoids, phenolic acids, terpenoids and other bioactive compounds, effectively attenuate NLRP3 activation by suppressing NF-κB-dependent priming, limiting mitochondrial ROS generation, stabilising lysosomal integrity, enhancing AMPK-SIRT signalling and promoting autophagy. Several plant extracts and complex formulations exhibit coordinated metabolic and anti-inflammatory benefits across adipose, hepatic, vascular, neural and renal models of MetS. In addition to summarising their regulatory effects on key inflammatory and metabolic pathways, the review also addresses available toxicity and safety data, thereby providing a more comprehensive perspective on their therapeutic relevance. Overall, this review presents an integrated synthesis of mechanistic and preclinical evidence highlighting natural products as multi-target modulators of NLRP3-mediated metabolic inflammation.

Keywords:  Flavonoids; Inflammation; Insulin resistance; Obesity; Phytochemicals

DOI:  https://doi.org/10.1007/s00011-026-02253-2
Cells. 2026 Apr 17. pii: 713. [Epub ahead of print]15(8):

Elevation of Mitochondrial Ca2+ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse Soleus Muscle.

Joseph Bruton, Kent Jardemark.

  Soleus muscle fibres display modest changes in tetanic force and [Ca2+]i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca2+ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus muscles of adult mice. Mitochondrial Ca2+ was measured with rhod-2 in intact fibres. Fatigue was induced by 70 Hz, 350 ms tetani given at 2 s intervals in the absence and presence of 10 µM CGP-37157, a potent inhibitor of the mitochondrial Na+-Ca2+ exchanger. In soleus fibres fatigued in the absence of CGP-37157, tetanic force was significantly reduced by about 30% at the end of the fatiguing stimulation, while mitochondrial [Ca2+] increased to a maximum after about 50 tetani and returned to its resting level within 20 min after the end of the stimulation. In the presence of CGP-37157, the maximal mitochondrial [Ca2+] increase was more than twice that in control fibres. In addition, fatigue developed more rapidly and force remained depressed after the end of the stimulation. No difference in mitochondrial membrane potential or ROS production was seen between control and CGP-37157 conditions. We conclude that while modest increases in mitochondrial Ca2 may be beneficial, excessive mitochondrial Ca2 loading depresses muscle function.

Keywords:  Ca2+; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3390/cells15080713
Front Nutr. 2026 ;13 1802531

The effect of exogenous ketone bodies on cognition across health and disease: a systematic review and meta-analysis.

Bruno Bonnechère, Elizabeth B Stephens, Amy C Boileau, Martin Ducker, Brianna J Stubbs.

   Introduction: Cognitive function is closely linked to brain energy metabolism and may be compromised by aging, metabolic stress, and neuropsychiatric disease. Ketone bodies can serve as an alternative cerebral fuel and may also exert signaling effects relevant to cognition. Exogenous ketones (EK) offer a practical means of increasing circulating ketone concentrations without dietary carbohydrate restriction. However, the overall effect of EK supplementation on cognitive performance in humans has not been systematically quantified.
Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Web of Science, and Embase were searched through October 2025 for randomized controlled trials investigating the effects of EK on cognitive outcomes in healthy adults or individuals with neuropsychiatric conditions. Data extraction and quality assessment were performed independently by multiple reviewers using the PEDro scale. Standardized mean differences (SMD) were calculated using random-effects models. Subgroup and meta-regression analyses examined the influence of ketone formulation, intervention duration, dose, population type, and presence of acute cognitive stressors.
Results: 38 studies comprising 41 protocols (1,602 participants) were included in the systematic review, with 29 protocols (1,117 participants) eligible for meta-analysis. EK supplementation was associated with a statistically significant improvement in cognitive performance compared with placebo (SMD = 0.29, 95% CI 0.16-0.41; p < 0.001). Sub-group analyses did not show statistically significant differences between the type of supplementation (p = 0.083), study duration (acute vs. intermediate; p = 0.11), population type (healthy vs. Alzheimer's disease; p = 0.077), or the presence of acute cognitive stressors (p = 0.89). Meta-regression revealed a positive association between daily EK dose and cognitive improvement.
Discussion: EK supplementation is associated with modest improvements in cognitive performance across diverse populations and study designs. These findings support EK as a flexible nutritional strategy for cognitive support and warrant further investigation in well-powered, long-term trials to clarify optimal dosing, formulation, and clinical applicability.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42023471727, CRD42023471727.

Keywords:  D-β-hydroxybutyrate; cognition; ketone ester; ketones; meta-analysis

DOI:  https://doi.org/10.3389/fnut.2026.1802531
J Nutr Sci. 2026 ;15 e26

The impact of dietary phosphorus supplementation on postprandial metabolic outcomes: a systematic review.

Rania El Khoury, Omar A Obeid, Simon Welham, Amanda Avery.

  Given the central role of phosphorus in key metabolic processes, including glucose phosphorylation, ATP synthesis, insulin signalling, and energy metabolism, dietary phosphorus availability may influence postprandial metabolic responses. This systematic review evaluates the effects of inorganic phosphorus supplementation on diet-induced thermogenesis, postprandial glycaemia, and postprandial lipidemia in healthy adults. A systematic search of PubMed, Google Scholar, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. Only experimental intervention studies assessing phosphorus supplementation as the primary exposure and postprandial metabolic outcomes as primary endpoints were included. Eligible participants were healthy adults aged 18-64 years. Secondary outcomes included changes in body weight, energy intake, and satiety. Ten randomised crossover trials met inclusion criteria, comprising a total of 225 participants. Three out of four studies reported a significant positive association between phosphorus supplementation and diet-induced thermogenesis (P < 0.05). Evidence regarding the effects of phosphorus on postprandial glycaemia and lipidemia was inconsistent. An inverse association was observed between phosphorus intake and weight gain (P < 0.001) and energy intake (P < 0.01), alongside a positive association with satiety (P < 0.05). While these findings indicate potential metabolic benefits of dietary phosphorus, particularly in relation to thermogenesis and energy regulation, interpretation is tempered by the small number of available studies, modest sample sizes, and methodological heterogeneity. These limitations restrict causal inference and generalizability. Further rigorously designed, adequately powered clinical trials are therefore warranted to substantiate these associations and to clarify the effects of phosphorus on postprandial glycaemic and lipid outcomes.

Keywords:  Glycaemia; lipidemia; metabolism; phosphorus; thermogenesis

DOI:  https://doi.org/10.1017/jns.2026.10094
J Mol Neurosci. 2026 Apr 27. pii: 70. [Epub ahead of print]76(2):

Nicotinamide Riboside (NR) Supplementation Exerts Neuroprotective Effects in db/db Mouse Model of Type 2 Diabetes.

Eleni Hughes, Keely Barton, Daliya Rizvi, Katelyn Dial, Xiaoxin X Wang, Komuraiah Myakala, Brent T Harris, G William Rebeck, Moshe Levi.

  Type 2 diabetes is linked to neuropsychiatric complications such as anxiety-like behaviors, disrupted brain metabolism, neuroinflammation, and impaired mitochondrial function. Nicotinamide riboside (NR) has emerged as a potential therapeutic agent for these complications due to its role in NAD + biosynthesis and neuroprotective properties. In this study, we assessed whether NR supplementation can ameliorate anxiety-like behavior in a mouse model of type 2 diabetes by modulating the hippocampal inflammatory response. 8-week-old db/db mice on the BKS background were used as a model of type 2 diabetes, and db/m mice were used as non-diabetic controls. Four groups, consisting of non-diabetic and diabetic mice, were fed with a control diet or a diet supplemented with NR at 500 mg/kg dosage for 20 weeks. The open field test and nesting behavioral assessments were conducted to evaluate anxiety-related behaviors and overall well-being. After animals were euthanized, biochemical analyses were performed on hippocampal samples using RT-qPCR, Western blotting, and immunohistochemistry. Behavioral assessments revealed increased anxiety and reduced nest-building motivation in db/db mice compared with control mice. These effects were ameliorated by NR treatment. Biochemical analyses revealed that NR attenuated markers of inflammation, including astrocytosis and microglial activation, activation of inflammatory signaling via STING and NF-kB, and pro-inflammatory cytokines. Our findings show that NR supplementation reduces anxiety-like symptoms and neuroinflammation in diabetic mice, highlighting the potential therapeutic relevance of NR in mitigating neuropsychiatric complications associated with diabetes mellitus.

Keywords:  Diabetes; NAD + ; Neuroinflammation; Nicotinamide Riboside

DOI:  https://doi.org/10.1007/s12031-026-02499-9
Alzheimers Dement. 2026 May;22(5): e71360

NAD+‒circadian rhythm coupling in dementia.

Shi-Qi Zhang, Jiyeon Lee, Jun-Ping Pan, Rune Enger, Harald Hrubos-Strøm, Erik S Musiek, Evandro Fei Fang, Weidong Le.

  The circadian rhythm system and sleep coordinate whole-body functions across the 24-h cycle, yet these rhythms progressively deteriorate with neurodegenerative diseases, including dementia. Growing evidence indicates that nicotinamide adenine dinucleotide (NAD+) interacts with the circadian system through multiple molecular pathways and that NAD+ levels decline with dementia. In this review, we synthesize current evidence on the bidirectional relationship between NAD+ metabolism and circadian regulation in several dementia disorders, emphasizing the key circadian pathways, the nicotinamide phosphoribosyltransferase-mediated salvage synthesis, the NAD+/sirtuins-dependent signaling, and the consumption of NAD+ by PARP1 and CD38. Finally, we also examine pharmacological and lifestyle strategies that target NAD+, including NAD+ precursors, modulators of NAD+ biosynthetic and depleting enzymes, timed light and activity exposure, structured exercise programs, and dietary interventions. Overall, we focus on the bidirectional interplay between NAD+ metabolism and circadian rhythm regulation in dementia, with particular emphasis on how this interaction influences sleep and cognitive phenotypes across different dementia subtypes. Trial Registration: ClinicalTrials.gov identifier: NCT05040321, NCT04430517, NCT06971224, NCT05500170, NCT04070378.

Keywords:  CD38; NAD+; PARP1; SIRT1; circadian rhythm; dementia; sleep

DOI:  https://doi.org/10.1002/alz.71360
Neurosci Lett. 2026 Apr 28. pii: S0304-3940(26)00115-1. [Epub ahead of print] 138616

Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.

Sergej M Ostojic, Jelena Ostojic.

   BACKGROUND: Menopause and the perimenopausal transition involve profound hormonal and metabolic changes that may impair brain function. Beyond structural alterations, reduced cerebral bioenergetics could underlie the cognitive complaints often reported during this period. Because creatine serves as a key neuronal energy buffer and is influenced by estrogen, this study examined brain creatine concentrations in perimenopausal women and their associations with neurocognitive symptoms and serum estradiol.
METHODS: Twelve healthy perimenopausal women (mean age 49.8 ± 5.4 years) experiencing irregular cycles and at least one perimenopausal symptom underwent multi-voxel 1H-magnetic resonance spectroscopy to quantify total brain creatine across bilateral frontal, precentral, and parietal gray- and white-matter regions and the thalamus. Serum estradiol was measured by ELISA, and symptom severity was rated on visual analog scales. Associations were assessed using Kendall's τ.
RESULTS: Mean whole-brain creatine concentration (6.31 ± 0.98 mM) was significantly lower than reference values in younger adults (Z = -1.65, P = 0.049). Lower creatine levels in the thalamus, right precentral, and right parietal white matter correlated with greater concentration difficulties (τ = -0.38 to -0.51, P ≤ 0.049), while right frontal white-matter creatine positively correlated with headache severity (τ = 0.41, P = 0.034). Serum estradiol averaged 119.5 ± 109.5 pg/mL and was inversely associated with right parietal gray-matter creatine (τ = -0.37, P = 0.049).
CONCLUSIONS: Perimenopausal women exhibited lower cerebral creatine than younger adults, with region-specific reductions linked to concentration difficulties and estradiol levels. These findings suggest that estrogen-related changes in brain bioenergetics may contribute to cognitive symptoms during the menopausal transition.

Keywords:  Bioenergetics; Creatine; Estradiol; MRS; Neurocognitive; Perimenopause

DOI:  https://doi.org/10.1016/j.neulet.2026.138616
Transl Neurodegener. 2026 Apr 27. pii: 18. [Epub ahead of print]15(1):

The Drp1-CoQ10-Coa6-ETC axis represents a therapeutic potential for working memory impairment caused by neuronal mitochondrial dysfunction.

Jingjing Tie, Shujiao Li, Xin Huang, Keke Ren, Ziwei Ni, Xiaodong Li, Changlei Zhu, Hui Liu, Feifei Wu, Yanling Yang, Yayun Wang.

   BACKGROUND: Coenzyme Q10 (CoQ10) is a key mitochondrial electron carrier and a widely used dietary supplement with potential neurological benefits. However, the mechanisms underlying its effect in ameliorating memory deficits caused by cerebellar injury are not fully understood. In this study, we investigated the effects of long-term CoQ10 supplementation on working memory and the underlying mechanisms.
METHODS: Network pharmacology analysis was used to identify genetic targets of CoQ10 in cerebellar injury-related cognitive impairment. Purkinje cell (PC)-specific Drp1-deficient mice (PC-Drp1-/-) were generated to model mitochondrial dysfunction. Behavioral performance was evaluated using the eight-arm radial maze. Mitochondrial structure and respiratory chain complex levels were evaluated by morphological and biochemical assays. Molecular targets of CoQ10 were identified using integrated drug-target engagement approaches, and their functional relevance was tested by viral vector-mediated overexpression.
RESULTS: The PC-Drp1-/- mice displayed progressive working memory impairment and decreased PC density, accompanied by disrupted mitochondrial morphology and reduced activities of electron transport chain complexes III-V. Long-term CoQ10 treatment significantly reduced working memory errors and preserved PC numbers in PC-Drp1-/- mice. Target engagement analyses identified cytochrome c oxidase assembly factor 6 (Coa6) as a direct binding target of CoQ10. Viral vector-mediated overexpression of Coa6 in PCs partially recapitulated the CoQ10-associated improvements in respiratory chain complex levels and working memory, whereas Coa6 knockdown attenuated these benefits.
CONCLUSIONS: CoQ10 directly interacts with Coa6 to enhance mitochondrial respiratory chain function and preserve PC integrity in the context of Drp1 deficiency. Our findings suggest a promising mechanistic pathway for CoQ10-based intervention in memory deficits associated with mitochondrial dysfunction.

Keywords:  Coenzyme Q10; Cytochrome c oxidase assembly factor 6; Dynamin-related protein 1; Purkinje cells; Working memory

DOI:  https://doi.org/10.1186/s40035-026-00552-6
Phytomedicine. 2026 Apr 15. pii: S0944-7113(26)00417-4. [Epub ahead of print]156 158183

Astragaloside IV delays vascular aging by enhancing mitochondrial fatty acid β-oxidation via the MLXIPL-PPARα/PGC-1α axis.

Xiangyu Chen, Xiaodie Chen, Nan Xiao, Yutong Yang, Chenghui Li, Yanbin Pan, Huiqun Huang, Xiaodong Duan, Yongan Deng, Chengkai Chen, Shuting Zeng, Simin Yang, Yixuan Huang, Danping Huang, Yubin Yang, Zunpeng Shu, Li Zhang.

   BACKGROUND: Mitochondrial dysfunction and the dysregulation of lipid metabolism are significant contributors to vascular aging, which in turn raises the risk of age-related cardiovascular diseases (CVDs). Buyang Huanwu decoction (BHD), a traditional formula widely used for treating CVDs, has not been thoroughly investigated in terms of its active components and the molecular mechanisms by which it may delay vascular aging.
PURPOSE: This study aims to investigate the effects and mechanisms of BHD and its primary active component, Astragaloside IV (AS-IV), in mitigating vascular aging, focusing on mitochondrial function and lipid metabolism.
METHODS: Experiments were conducted using naturally aged mice and a D-galactose-induced model of vascular smooth muscle cells (VSMCs) senescence. Vascular aging was evaluated through aortic histopathology, assessment of senescence markers and senescence-associated secretory phenotype (SASP) factors. Transcriptomics and lipidomics analyses were employed to uncover critical pathways and identify differential lipid profiles. Mitochondrial structure and function were examined using transmission electron microscopy (TEM), Mitochondrial DNA (mtDNA) copy number, and mitochondrial membrane potential (MMP). The molecular mechanisms were further validated through molecular biology and MLX Interacting Protein-Like (MLXIPL) knockdown and overexpression techniques.
RESULTS: Both BHD and AS-IV improved age-related vascular morphological changes, mitigated elastic fiber disruption, diminished collagen deposition, and downregulated senescence markers along with SASP factors. Transcriptomic analysis identified MLXIPL as a key transcription factor, emphasizing the involvement of the peroxisome proliferator-activated receptor (PPAR) signaling pathway and mitochondrial fatty acid β-oxidation as critical processes. Lipidomic profiling indicated reduced serum acylcarnitine levels in aged mice, suggesting compromised fatty acid β-oxidation. Both BHD and AS-IV were found to suppress MLXIPL, activate PPARα, increase mtDNA copy number, enhance MMP, improve mitochondrial ultrastructure, and upregulate the expression of key genes and proteins associated with mitochondrial biogenesis and fatty acid β-oxidation. Co-immunoprecipitation assays confirmed that AS-IV facilitated PPARα-PGC-1α interaction. Functional validation established that MLXIPL knockdown produced a stronger effect than AS-IV, whereas MLXIPL overexpression negated the beneficial effects of AS-IV on mitochondrial function, lipid accumulation, and cellular senescence.
CONCLUSION: BHD and its active component AS-IV delay vascular aging by inhibiting MLXIPL, thereby activating the PPARα/PGC-1α signaling pathway to promote mitochondrial fatty acid β-oxidation and reduce lipid accumulation. This elucidates a mechanistic basis for BHD's traditional use and highlights AS-IV as a key active principle with therapeutic potential.

Keywords:  Astragaloside IV; Buyang Huanwu decoction; Fatty acid β-oxidation; Lipid metabolism; Mitochondrial biogenesis; Vascular aging

DOI:  https://doi.org/10.1016/j.phymed.2026.158183