bims-mistre 2025-10-12 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–10–12
twenty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

The energy resistance principle.
Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.
Mitochondrial dysfunction in PTSD: A mechanism to understand trauma susceptibility?
Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.
Role of telomere length and telomerase activity in accelerated cellular aging and major depressive disorder: a systematic review.
Advancements in Understanding the Role and Mechanisms of Mitochondria in Diabetes: A Comprehensive Review.
Salivary mitochondrial DNA is associated with biomarkers of Alzheimer's disease in cognitively normal older adults.
Decreased Mitochondrial DNA Integrity and Elevated Inflammatory Markers in Late-Life Depression: A Longitudinal Study.
Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.
Reviving the Mitochondria: A Hopeful Horizon in Refractory Heart Failure.
Sex Differences in Renal Mitochondrial Respiration and H2O2 Emission in Young Dahl Salt-Sensitive Rats.
Neurons in Need: Glucose, but Not Lactate, Is Required to Support Energy-Demanding Synaptic Transmission.
Investigation of ovarian aging markers and hormonal regulation in menopausal transition.
Chrysin, a glycolytic inhibitor, modulates redox homeostasis during aging via a potent calorie restriction mimetic effect in male wistar rats.
Mitochondrial Ca2+ uniporter haploinsufficiency leads to sexually dimorphic redox imbalance and metabolic remodelling in the mouse brain.
Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner.
Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.
Dual-targeting antioxidant and anti-glycation strategy inhibits melanogenesis through clinical and mechanistic study.
Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens.
Resisting decline: the neuroprotective role of resistance exercise in supporting cerebrovascular function and brain health in aging.
Multifaceted mitochondria in innate immunity.

Cell Metab. 2025 Oct 06. pii: S1550-4131(25)00387-0. [Epub ahead of print]

The energy resistance principle.

Martin Picard, Nirosha J Murugan.

  Living organisms are physical-energetic systems that must obey simple principles guiding energy transformation across physical and temporal scales. The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. Although éR is required to sustain life, excess éR directly causes reductive and oxidative stress, heat, inflammation, molecular damage, and information loss-all hallmarks of disease and aging. We discuss how disease-causing stressors elevate éR and circulating growth differentiation factor 15 (GDF15) levels, whereas sleep, physical activity, and restorative interventions that promote healing minimize éR. The ERP is a testable general framework for discovering the modifiable bioenergetic forces that shape development, aging, and the dynamic health-disease continuum.

Keywords:  GDF15; biological circuits; biomarkers; cytokines; disease; energy; exercise; healing; inflammation; mitochondria; oxygen; physical laws; transformation

DOI:  https://doi.org/10.1016/j.cmet.2025.09.002
J Neurochem. 2025 Oct;169(10): e70252

Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.

Leyre Sánchez de Muniain, Paula Escalada, María J Ramírez, Maite Solas.

  Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.

Keywords:  aging; allostasis; glycolysis; hypermetabolism; neurodegeneration

DOI:  https://doi.org/10.1111/jnc.70252
Psychopharmacology (Berl). 2025 Oct 10.

Mitochondrial dysfunction in PTSD: A mechanism to understand trauma susceptibility?

Felippe E Amorim, Charlotte S Rye, Amy L Milton.

   RATIONALE AND OBJECTIVES: Post-Traumatic Stress Disorder (PTSD) is a complex mental health condition that arises following exposure to traumatic events. Converging evidence suggests mitochondrial dysfunction and brain energy metabolism impairment in its pathophysiology. Thus, examining mitochondrial data from both preclinical and experimental medicine studies may help us to have a deeper understanding of the pathophysiological mechanisms underlying PTSD.
METHODS: Using PubMed, Scopus and Web of Science online databases, we conducted a search for peer-reviewed manuscripts targeting both mitochondrial-related activity and PTSD. Our search yielded 43 studies in total, including 29 in rodent models and 15 clinical studies.
RESULTS: Preclinical studies reported a decrease in energy metabolism with a reduction in adenosine triphosphate (ATP) level, upregulation of genes associated with ATP synthesis, impairment of the glycolytic pathway, citric acid cycle and oxidative phosphorylation pathways and increased oxidative stress and neuronal apoptosis in the brain, or systemically. In the clinical setting, studies identified 1108 participants with PTSD and 312 with partial PTSD, with these individuals showing alterations in energy production, mitochondrial DNA copy number (mtDNAcn) and elevated oxidative stress. Risperidone and AC-5216-a selective ligand for TSPO-emerged as potential treatments.
CONCLUSION: Our synthesis of the published findings indicates a notable overlap between results from both animal models and humans which could show a potential usage of mitochondrial-related targets as biomarkers or for drug discovery. Additionally, these results highlight the need for future research in describing whether mitochondrial dysfunction is a cause or a symptom of PTSD.

Keywords:  Inflammation; Metabolism; Mitochondria; Oxidative Stress; PTSD

DOI:  https://doi.org/10.1007/s00213-025-06900-0
Front Neuroendocrinol. 2025 Oct 03. pii: S0091-3022(25)00043-3. [Epub ahead of print] 101217

Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.

George B Stefano, Pascal Büttiker, Simon Weissenberger, Jiri Raboch, Martin Anders.

  While mitochondria provide critical energy resources, mitochondrial dysfunction can lead to both metabolic and neurodegenerative disorders. Primary mitochondrial disorders (e.g., Leigh syndrome) are uniformly associated with profound neurodegeneration. Recent studies have also implicated mitochondrial dysfunction as a central feature of progressive neurodegenerative diseases, notably Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's Disease. In addition to its profound impact on metabolic disease, the glucagon-like peptide-1 receptor agonist, semaglutide, has significant neuroprotective features and may limit the progression of one or more of these disorders. These observations might be explained at least in part by the impact of this drug on mitochondrial function and energy production. Collectively, these observations highlight disrupted energy homeostasis as a critical feature of neurodegenerative disease and suggest novel targets for the development of much-needed new neuropharmaceutical strategies.

Keywords:  Alzheimer’s disease; Glucagon-like Peptide 1; Mitochondria; Neurodegenerative disease; Oxidative phosphorylation; Parkinson’s disease; Semaglutide

DOI:  https://doi.org/10.1016/j.yfrne.2025.101217
Mol Psychiatry. 2025 Oct 07.

Role of telomere length and telomerase activity in accelerated cellular aging and major depressive disorder: a systematic review.

Samantha Wai Sam Au Young, Chuin Hau Teo, Ishwar S Parhar, Tomoko Soga.

Recent research has increasingly focused on understanding the relationship between cellular aging and mental health, particularly Major Depressive Disorder (MDD). Telomeres, protective structures at the end of chromosomes, and telomerase, an enzyme responsible for their maintenance, have emerged as potential markers of cellular aging and targets for therapeutic interventions in MDD. This review synthesizes findings from 30 studies conducted over the past 15 years, examining alterations in telomere length (TL) and telomerase activity (TA) in individuals with MDD compared to healthy controls. Most studies reported shorter TL in MDD patients, particularly in cases of chronic or severe depression, determined by the duration of illness or illness episode and by measurements of depression severity (e.g. HAM-D, BDI, etc.), suggesting an association between MDD and accelerated cellular aging. Elevated TA was also observed in MDD, with potential implications for treatment response. However, conflicting findings and methodological variations highlight the complexity of the relationship between TL, TA, and MDD, warranting further research. Additionally, studies investigating other biomarkers of cellular aging, such as mitochondrial DNA, provide further insights into the pathophysiology of MDD. Studies on brain cells reveal regional variations in telomere dynamics, suggesting a nuanced relationship between depression and cellular aging across different brain regions. While evidence suggests a potential reversibility of TL alterations in MDD, further research is needed to elucidate underlying mechanisms and develop targeted interventions. Overall, this review underscores the importance of understanding cellular aging processes in MDD and their potential implications for diagnosis, treatment, and the development of novel therapeutic strategies.

DOI: https://doi.org/10.1038/s41380-025-03296-3
J Steroid Biochem Mol Biol. 2025 Oct 06. pii: S0960-0760(25)00203-1. [Epub ahead of print] 106875

Advancements in Understanding the Role and Mechanisms of Mitochondria in Diabetes: A Comprehensive Review.

Xia Ge, Min Ye, Aihua Fei, Qingping Zhang, Aihong Yuan.

  Diabetes mellitus is a global health crisis with a rising prevalence attributed to complex interactions of genetic, lifestyle, and environmental factors. This comprehensive review delves into the pivotal role of mitochondrial dysfunction in the onset and progression of diabetes. It outlines how defects in mitochondrial oxidative phosphorylation, increased free radical production, and mitochondrial DNA damage contribute to insulin resistance, β-cell apoptosis, and systemic metabolic dysfunctions. The review highlights the critical roles of mitochondria in energy metabolism, oxidative balance, and the interplay of genetic and environmental factors in diabetes. It also emphasizes the association of impaired mitochondrial function with various diabetes-related complications and organ-specific diseases, underscoring the urgent need for innovative therapeutic strategies. Potential interventions discussed include pharmacological agents promoting mitochondrial biogenesis and enhancing mitochondrial dynamics, alongside dietary and lifestyle modifications that support mitochondrial function and overall metabolic health. The review calls for intensified research into mitochondrial mechanisms and their therapeutic targets, advocating for comprehensive clinical trials and support from medical and governmental institutions to advance diabetes management strategies centered on mitochondrial health.

Keywords:  Diabetes metabolism; Mechanism interventions; Mitochondria

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106875
Transl Psychiatry. 2025 Oct 06. 15(1): 355

Salivary mitochondrial DNA is associated with biomarkers of Alzheimer's disease in cognitively normal older adults.

Jose L Cantero, Mercedes Atienza, Petar Podlesniy, Margalida Puigròs, Ramon Trullas.

A significant body of evidence suggests that mitochondrial dysfunction plays a key role in the development and progression of Alzheimer's disease (AD). However, the absence of peripheral biomarkers for mitochondrial dysfunction limits its clinical applicability. Mitochondrial DNA (mtDNA) copy number, a proxy for mitochondrial function, has shown promise in detecting early stages of AD and predicting AD risk in cerebrospinal fluid (CSF) and blood, respectively. Surprisingly, recent studies have identified mtDNA molecules in human saliva, but their relationship with AD remains unexplored. Here, we investigated potential associations between salivary mtDNA copy number and cortical amyloid-β (Aβ) load measured with PET, and blood AD markers measured with ultrasensitive single molecule array (SIMOA) assays, in cognitively normal older adults. We found that salivary mtDNA copy number was positively correlated with cortical Aβ burden and plasma levels of tau phosphorylated at threonine 181 (pTau-181), and negatively correlated with general cognitive ability. It is worth noting that salivary mtDNA was not significantly associated with other blood-based AD biomarkers, including Aβ1-40, Aβ1-42, neurofilament-light chain (NfL), or glial fibrillary acidic protein (GFAP). Additionally, plasma pTau-181 levels moderated the association between salivary mtDNA and Aβ accumulation in the inferior temporal lobe, while Aβ load in the occipital cortex mediated the association between plasma pTau-181 and salivary mtDNA. Together, these findings represent the first evidence linking salivary mtDNA to well-established AD biomarkers in normal aging, suggesting that salivary mtDNA may serve as a potential non-invasive biomarker for identifying individuals at risk for developing AD in the general population.

DOI: https://doi.org/10.1038/s41398-025-03589-9
Biol Psychiatry Glob Open Sci. 2025 Nov;5(6): 100598

Decreased Mitochondrial DNA Integrity and Elevated Inflammatory Markers in Late-Life Depression: A Longitudinal Study.

Ana Paula Mendes-Silva, Perla El-Ahmad, Ana Paula Costa, Lloyd Cenon Balbuena, Yuliya Stoycheva Nikolova, Tarek Rajji, James Lowery Kennedy, Erica Leandro Vieira, Vanessa Faria Gonçalves, Breno Satler Diniz.

   Background: Late-life depression (LLD) is a prevalent and severe mental disorder. The biological mechanisms underlying LLD are not fully understood, but increasing evidence suggests that mitochondria play a significant role. Impaired mitochondrial function leads to excessive production of reactive oxygen species and the release of circulating cell-free mitochondrial DNA (ccf-mtDNA). The ccf-mtDNA activates the toll-like receptor system, which triggers a systemic proinflammatory response. However, there is limited understanding of the impact of ccf-mtDNA integrity, such as deletions, on LLD pathological conditions.
Methods: We included 90 older individuals (50 LLDs, 40 nondepressed healthy control participants [HCs]), with a subset of individuals followed up at 30 months (13 LLDs, 13 HCs). Plasma was separated from blood, and DNA was extracted. Mitochondrial genes MT-ND2 and MT-ND4 were targeted to evaluate ccf-mtDNA levels and deletion using real-time quantitative polymerase chain reaction. Plasma interleukins (ILs) 1β, 5, and 6 were quantified via multiplex immunoassay.
Results: LLD was linked to increased ccf-mtDNA instability at baseline (deletion: F 88,1 = 7.105, p = .009; levels: F 88,1 = 6.885, p = .01), which was associated with more severe depressive symptoms and greater medical comorbidity burden. Longitudinal analysis revealed significant effects of diagnosis and time on ccf-mtDNA levels and the deletion rate. Additionally, higher deletion rates at baseline predicted IL-5 and IL-6 levels at 30 months (p adjusted = .13, p adjusted = .12, respectively).
Conclusions: Increased ccf-mtDNA instability may heighten vulnerability to emotional dysregulation and medical burden in individuals with LLD. Further research is needed to validate our findings and elucidate the mechanisms that connect mitochondrial instability and inflammation in LLD.

Keywords:  Extracellular DNA; Gene deletion; Inflammation; Major depressive disorder; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.bpsgos.2025.100598
Neurosci Lett. 2025 Oct 06. pii: S0304-3940(25)00299-X. [Epub ahead of print]868 138410

Mitochondrial dysfunction and aging can be alleviated by modulating calcineurin and cardiolipin dynamics following stroke.

Pallab Bhattacharya, Shailendra Saraf, Anirban Barik, Bijoyani Ghosh, Aishika Datta, Davendra Singh Malik.

  The crucial influence of mitochondria in ischemic stroke pathophysiology presents many unexplored yet promising avenues for therapeutic strategies and clinical outcomes. Post-stroke mitochondrial dysfunction contributes to aggravated levels of calcium overload and apoptosis. This dysfunction is signified by disruption of the mitochondrial lipids such as cardiolipin, along with mitochondrial DNA mutation, leading to an imbalance in mitophagy. Calcium overload-mediated calcineurin overexpression has been reported to exacerbate mitochondrial damage and further contribute to neuronal apoptosis. In our study, we explored the alterations in the mitochondrial function following inhibition of the calcium-mediated calcineurin levels in post-stroke condition. In a rodent model of middle cerebral artery occlusion (MCAo), we observed that the inhibition of the calcium channels in post-stroke condition led to restored neuronal histology and viability following upregulation of the antioxidant levels. At the mitochondrial level, calcium channel inhibition downregulated calcineurin activation and normalized cardiolipin concentration, mitochondrial membrane potential, and respiratory control ratio in post-stroke condition. This inhibition also balanced the mitochondrial dynamics proteins and mitophagy towards neuronal recovery following ischemic stress. Moreover, it also normalized the expression of TERT, a key marker of mitochondrial health and aging. These findings highlight the role of calcium-mediated calcineurin in influencing mitochondrial dysfunction and aging in ischemic stroke. Thus, calcium channel inhibition offers a promising therapeutic strategy by preserving mitochondrial integrity and promoting neuroprotection following stroke.

Keywords:  Calcineurin; Calcium signaling; Cardiolipin; Mitochondrial aging; Stroke

DOI:  https://doi.org/10.1016/j.neulet.2025.138410
Cureus. 2025 Sep;17(9): e91710

Reviving the Mitochondria: A Hopeful Horizon in Refractory Heart Failure.

Zeeshan Ahmed, Fnu Abdul Rehman, Syed Faqeer Hussain Bokhari.

  Refractory heart failure (HF) remains a pressing clinical challenge despite substantial progress in pharmacologic and device-based interventions. While current therapies target neurohormonal, hemodynamic, and metabolic derangements, a crucial element of cellular dysfunction often remains overlooked: mitochondrial health. Mitochondrial dysfunction plays a central role in the pathogenesis and progression of HF, contributing to bioenergetic failure, oxidative stress, and cardiomyocyte death. Recent advances in mitochondrial-targeted therapies have opened new possibilities for treating HF at its energetic roots. This editorial explores the pathophysiological role of mitochondria in HF, reviews emerging therapeutic strategies aimed at restoring mitochondrial function, and outlines key challenges that must be addressed to translate these innovations into clinical practice.

Keywords:  elamipretide; heart failure; mitochondira; mitoq; perhexiline; pgc-1α; trimetazidine; urolithin

DOI:  https://doi.org/10.7759/cureus.91710
Function (Oxf). 2025 Oct 07. pii: zqaf045. [Epub ahead of print]

Sex Differences in Renal Mitochondrial Respiration and H2O2 Emission in Young Dahl Salt-Sensitive Rats.

Chun Yang, Devanshi D Dave, Sri Rahavi Boovarahan, Satoshi Shimada, Aron Geurts, Ranjan K Dash, Allen W Cowley.

  Sexual dimorphism has a significant influence on physiology, disease susceptibility, and therapeutic responses, yet its impact on kidney mitochondrial function remains poorly understood. We hypothesized that sex differences in kidney mitochondrial function would parallel those observed in other organs, where females often exhibit higher oxidative capacity and lower oxidative stress. To test this, we measured the kinetics of oxidative phosphorylation (OXPHOS) and hydrogen peroxide (H2O2) emission in isolated cortical and outer medullary (OM) mitochondria from young male and female Dahl salt-sensitive (SS) rats fed a low-salt diet. Contrary to our hypothesis, male cortical mitochondria showed significantly higher O2 consumption during ATP synthesis (OXPHOS) than females when fueled by either complex I- or complex II-linked substrates. Cortical H2O2 emission was also greater in males, under both forward and reverse electron transport fueled by succinate. This difference was consistent with an increase in Complex IV protein abundance despite no changes in mitochondrial DNA copy number or markers of mitochondrial dynamics. In the OM, both mitochondrial respiration and H2O2 emission were higher than in the cortex, but no sex differences were observed. Analysis of kidney transporter protein abundance revealed a sex-specific "downstream shift" in nephron transport function. Males showed a greater sodium reabsorption potential in the proximal tubules (PT) and reduced capacity in distal segments. The elevated cortical OXPHOS activity in males likely supports these higher PT transport demands. These results indicate that sex differences in renal mitochondrial function diverge from those in other organs, suggesting that kidney-specific energetic demands override systemic maternal inheritance and sex hormone effects. The higher cortical H2O2 emission in males may contribute to a greater susceptibility to kidney injury and salt sensitivity.

Keywords:  Oxidative stress; Proximal tubular transport; Reactive oxygen species; Renal metabolism; Sex differences, Mitochondrial bioenergetics

DOI:  https://doi.org/10.1093/function/zqaf045
J Neurochem. 2025 Oct;169(10): e70255

Neurons in Need: Glucose, but Not Lactate, Is Required to Support Energy-Demanding Synaptic Transmission.

Jens V Andersen, Mary C McKenna.

  The brain derives its energy from a combination of several metabolic substrates. The principal energy substrate of the brain is glucose, but the metabolic role of cerebral lactate has been debated for decades. In particular, the hypothesis that astrocyte-derived lactate is needed to fuel neuronal metabolism during activation remains a heated topic. This Editorial highlights a study in the current issue of Journal of Neurochemistry exploring the metabolic relationship between glucose and lactate metabolism in sustaining neuronal network signaling. The study by Söder et al. demonstrates that neurons are only able to sustain energy-demanding synchronized synaptic transmission when glucose is freely available. Blocking lactate transport had no effect on neuronal signaling when glucose was present, highlighting that any potential transfer of lactate is not required during high neuronal workload. In fact, when lactate was supplied as the primary fuel, neurons were unable to sustain synchronized signaling. Using a lactate biosensor, the authors further show that neurons produce and release lactate, both during resting and stimulated conditions. As synchronized synaptic transmission underlies higher brain function, this paper underscores the absolute necessity of neuronal glucose metabolism to maintain brain function.

Keywords:  astrocyte‐neuron lactate shuttle hypothesis; brain energy metabolism; glucose metabolism; metabolic shuttles; neuronal signaling

DOI:  https://doi.org/10.1111/jnc.70255
Cell Mol Biol (Noisy-le-grand). 2025 Oct 07. 71(9): 117-124

Investigation of ovarian aging markers and hormonal regulation in menopausal transition.

Samah Amer Hammood, Noor Alamer, Mohammed Kareem S ALquraish, Mohauman M Majeed.

Menopause and ovarian dysfunction are consequences of ovarian aging, a continuous and natural process in women. Early symptoms of ovarian aging include inadequate response to ovarian stimulation, irregular menstruation, and loss of follicular function, which collectively contribute to a decline in fertility as women age. The effects of aging on the ovaries are more pronounced than on other organs, with deterioration in the follicular pool and oocyte quality influenced by endocrine, genetic, and metabolic factors. This study aimed to examine the correlation between menopausal symptoms and serum levels of vitamin D, anti-Müllerian hormone (AMH), and other fertility-related hormones, as well as their impact on the timing of menopause. Ninety-two female participants were recruited from the Fertility Center Laboratories and AL-Saader Medical City in Al-Najaf province. A structured questionnaire assessing age, weight, height, and the severity of eleven menopausal symptoms-rated on a scale from 0 (absent) to 4 (extremely severe)-was administered. Symptoms evaluated included hot flushes, heart discomfort, sleep disturbances, muscle and joint pain, psychological issues, and urogenital problems. Serum levels of follicle-stimulating hormone (FSH), 25-hydroxyvitamin D, AMH, and luteinizing hormone (LH) were measured using the ELISA method. The results showed a significant negative correlation between serum AMH and vitamin D levels with menopausal symptoms and advancing age in postmenopausal women. Vitamin D levels were also negatively correlated with age, depression scores, and body mass index (BMI). Women with vitamin D deficiency and decreased AMH experienced more severe menopausal symptoms such as hot flushes, heart discomfort, depression, irritability, bladder problems, and musculoskeletal pain. These findings suggest that low AMH and vitamin D levels during menopause, compared to younger control women aged 20-40 years, may exacerbate menopausal symptoms. Supplementation with vitamin D, AMH, and reproductive hormone regulators, alongside lifestyle management, may benefit menopausal women suffering from fertility decline and severe menopausal symptoms.

DOI: https://doi.org/10.14715/cmb/2025.71.9.15
Biogerontology. 2025 Oct 07. 26(5): 188

Chrysin, a glycolytic inhibitor, modulates redox homeostasis during aging via a potent calorie restriction mimetic effect in male wistar rats.

Akanksha Singh, Sakshi Jaiswal, Raushan Kumar, Nitin Mishra, Sandeep Kumar Yadav, Syed Ibrahim Rizvi.

  Chrysin (5,7-dihydroxyflavone), a natural flavonoid present in honey, propolis, and various medicinal plants, has shown promise as a calorie restriction mimetic (CRM) through its glycolysis-inhibiting action. This inhibition promotes a metabolic shift toward oxidative phosphorylation and fatty acid oxidation, potentially activating beneficial pathways like AMPK and SIRT1. The mechanism likely involves the downregulation of Hexokinase-2, leading to suppressed glycolysis and promotion of apoptosis. In this study, we assessed aging biomarkers in erythrocytes, plasma, and serum after administering chrysin (100 mg/kg, orally) and D-galactose (300 mg/kg, subcutaneously) for four weeks to Wistar rats. In the D-galactose-induced aging rat model, the markers of oxidative damage, such as protein carbonyls, malondialdehyde, and advanced oxidation protein products, were found to be elevated. However, chrysin treatment significantly upregulated antioxidant defenses, including catalase, superoxide dismutase, ferric-reducing antioxidant power (FRAP), and glutathione (GSH). Administration of chrysin to aged rats led to a decline in both inflammatory biomarkers and insulin concentrations. These findings suggest that chrysin can alleviate oxidative stress, reduce lipid peroxidation, and influence inflammation and metabolism, highlighting its potential as an anti-aging therapeutic agent. This study underscores the potential of chrysin as a natural calorie restriction mimetic, mainly by maintaining redox balance by impacting longevity pathways and metabolic health.

Keywords:  Aging; Calorie Restriction Mimetics; Chrysin; D-galactose; Oxidative stress

DOI:  https://doi.org/10.1007/s10522-025-10334-8
J Physiol. 2025 Oct 09.

Mitochondrial Ca2+ uniporter haploinsufficiency leads to sexually dimorphic redox imbalance and metabolic remodelling in the mouse brain.

Jenna Gray, Girish Halemirle, Beatriz Ferrán, Hadyn Rose, Traci L Redwine, Sophia Pham, Bo Hagy, Atul Pranay, Jennifer Giorgione, Stacy A Hussong, Veronica Galvan, Kenneth Humphries, Holly Van Remmen, Mike Kinter, William E Sonntag, Pankaj K Singh, Carlos Manlio Díaz-García.

  The mitochondrial Ca2+ uniporter (MCU) links energy metabolism to cell excitability and signalling throughout the lifespan. However, whether neural metabolism responds to MCU impairments in a sex-specific manner has remained unknown, especially in models with partial MCU downregulation. Using hippocampal slices from adult heterozygous Mcu knock-out (hKO) mice, we observed sexually dimorphic changes in NAD(P)H autofluorescence dynamics following neuronal stimulation. In male mice, these signals were preserved despite decreased mitochondrial Ca2+ uptake, likely due to increased MDH2 levels and potentially other enzymes from the tricarboxylic acid cycle, the malate aspartate shuttle, and glycolysis. In contrast to males, neural tissue from female hKO mice showed delayed NAD(P)H production and limited NAD+ availability when compared to sex-matched controls, despite intact mitochondrial Ca2+ uptake. In addition, both male and female hKO mice exhibit decreased NADP+ levels and GSH/GSSG ratios (along with increased protein S-glutathionylation), indicating a weakened antioxidant capacity. Strikingly, markers of oxidative damage were also decreased (albeit more prominently in male mice), suggesting attenuated generation of reactive oxygen species. In addition, sex-specific changes in the hippocampal metabolome were manifested in hKO mice, along with a common decrease in spermidine levels. However, spermidine-dependent hypusination of eIF5A remained unaltered, suggesting further compensatory mechanisms at this age. In summary, our findings indicate that brain tissue can adapt to partial MCU deficits by salvaging most mitochondrial NADH production in active states, while compromising redox signalling and the polyamine pathway. The interplay between these molecular phenotypes likely impacts neurological conditions and potentially cognitive impairment with age. KEY POINTS: The inactivation of one Mcu allele (which encodes the mitochondrial Ca2+ uniporter) leads to altered neuronal excitability and attenuated mitochondrial Ca2+ elevations in active neurons from 6- to 12-months-old female and male mice, respectively. Tissue autofluorescence imaging reveals delayed mitochondrial NAD(P)H production in stimulated hippocampal tissue from female but not male heterozygous Mcu knockout mice. Mitochondrial Ca2+ uniporter haploinsufficiency is characterized by a sex-specific decrease in oxidative stress markers in the brain, despite a decline in NADP+ levels and the GSH/GSSG ratio in both male and female mice. Changes in the abundance of enzymes and polar metabolites in brain tissue reveal sexually dimorphic metabolic remodelling in the context of Mcu haploinsufficiency. Life-long downregulation of the mitochondrial Ca2+ uniporter results in decreased hippocampal spermidine levels in adult male and female mice.

Keywords:  NAD(P)H; brain metabolism; calcium; hippocampus; mitochondria; sexual dimorphism; spermidine

DOI:  https://doi.org/10.1113/JP287618
Alzheimers Dement (N Y). 2025 Oct-Dec;11(4):11(4): e70163

Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner.

Riley E Kemna, Amanda Szabo-Reed, Hana D Mayfield, Paul J Kueck, Jenae Pennington, Casey S John, Brittany M Hauger, Heather M Wilkins, Eric D Vidoni, Jill K Morris.

   INTRODUCTION: A sedentary lifestyle increases the risk for Alzheimer's disease (AD), whereas exercise has been shown to benefit brain health. Physiological factors, such as female sex, are linked to lower cardiorespiratory fitness and can increase the risk of AD, which might impact exercise benefits to the brain. Exploring cellular mechanisms underlying fitness in older adults is essential to understanding exercise and AD risk and how sex might impact this interaction.
METHODS: We collected blood from 34 cognitively healthy older adults (age 65+, 18 male, 16 female) enrolled in the COMbined Exercise Trial (COMET; NCT04848038). Subjects underwent a blood draw and clinical assessments for cardiorespiratory fitness and body composition. Blood was collected in ACD tubes, and lymphocytes were isolated. Fluorescent stains used were MitoTracker, Annexin V, MitoSOX, TMRE (tetramethylrhodamine ethyl ester), and Hoechst, analyzed by flow cytometry, and used to calculate a composite mitochondrial function index (MFI).
RESULTS: As expected, males had higher lean mass and VO2peak than females (p = 0.01), but groups did not differ in body mass index (p = 0.51). Males had a higher MFI compared to females (p = 0.01). Within each sex, we observed unique metabolic relationships. In males, there was an age-associated decline in MFI (R 2 = 0.382, p = 0.01). In females, our systemic measure of mitochondrial superoxides had a negative relationship with lean mass (R 2 = 0.648, p < 0.01) and oxygen uptake efficiency slope (OUES) (R 2 = 0.271, p = 0.04).
DISCUSSION: We combined an MFI with measures related to fitness in a cognitively healthy older adult population. We explored physiological factors that impact cardiorespiratory fitness, such as sex. We observed relationships between mitochondrial superoxides and OUES and lean mass in females, whereas males had higher MFI overall. Sex-dependent differences in mitochondrial function and superoxide might be an underlying factor of variable cardiorespiratory fitness between sexes and could help explain differences in AD risk.
Highlights: Mitochondrial blood-biomarker shows sex-dependent relationships in aging.Mitochondrial function index is higher in older adult males.Mitochondrial function index declines with age in males.Mitochondrial reactive oxygen species (ROS) are negatively associated with fitness in females.Mitochondrial ROS are negatively associated with lean mass in females.

Keywords:  Alzheimer's disease; exercise; metabolism; mitochondria; older adults; physical activity

DOI:  https://doi.org/10.1002/trc2.70163
Research (Wash D C). 2025 ;8 0912

Mitochondria Metabolism Regulates Glucose-Lipid Homeostasis in Neurodegenerative Diseases.

Jianliang Huang, Can Zhang, Cheng Huang, Kun Deng, Yun Xiao, Wei Gao, Minghua Wu, Mingsheng Lei.

Neurodegenerative diseases represent a major health threat, with dysfunction in energy metabolism and imbalance in glucose-lipid homeostasis constituting key pathogenic factors. As the cell's energy hub, mitochondria are closely associated with neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, the precise mechanism by which mitochondrial energy metabolism affects glucose-lipid homeostasis remains unclear. This review summarizes currents insights into the role of mitochondrial function in energy metabolism and glucose-lipid regulation in neurodegenerative diseases. We examined how mitochondrial dynamics, oxidative phosphorylation, calcium homeostasis, and key signaling pathways-AMP-activated protein kinase/mammalian target of rapamycin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and Sirtuin 1-contribute to neuronal energy balance and metabolic regulation. We further explored the impact of other organelles on mitochondria and how the dynamic switching of mitochondrial morphology and function disrupts the critical glucose-lipid homeostasis. By focusing on mitochondrial dysfunction, metabolic disorders, and their interactions, we introduce the mitochondria-centered multi-organelle-energy metabolic-glucose-lipid homeostasis (MMH) network as a unifying theoretical framework that positions the progressive loss of metabolic flexibility as the fundamental essence of neurodegenerative disorders. The MMH network furnishes a novel lens through which the shared mechanistic underpinnings of neurodegenerative diseases can be deciphered, and thereby enable earlier diagnosis and precision therapeutics.

DOI: https://doi.org/10.34133/research.0912
Sci Rep. 2025 Oct 09. 15(1): 35226

Dual-targeting antioxidant and anti-glycation strategy inhibits melanogenesis through clinical and mechanistic study.

Ying Ye, Jian Mu, Simin Lin, Tiantian Zhang, Fang Ye, Yuying Wang, Lingling Xuan, Changchang Chen, Panpan Yang, Jing Wang, Hu Huang.

  Hyperpigmentation constitutes a significant dermatological challenge, exacerbated by oxidative stress and glycation. This study aims to develop and evaluate a novel dual-effect composition (DEC) that integrates antioxidant agents (ergothioneine and tocopheryl glucoside) and antiglycation agents (decarboxy carnosine and naringin) for the management of hyperpigmentation. A multi-model approach was employed to comprehensively assess DEC efficacy. In vitro studies on A875 melanoma cells showed DEC lowered reactive oxygen species (ROS) level, enhanced Nrf2 and superoxide dismutase (SOD) expression, suppressed advanced glycation end-product (AGE)-RAGE signaling, and reduced tyrosinase (TYR) levels and melanin production. Using the MelaFulKutis™ 3D pigmented skin model under UV and methylglyoxal exposure, the DEC-containing serum also reduced melanin deposition and downregulated microphthalmia-associated transcription factor (MITF) and TYR expression by 63.37% and 80.39%, respectively. In a clinical trial involving 34 Asian participants, DEC-containing serum significantly improved skin lightness (ΔL*: +0.98%, P = 0.003), reduced facial sallowness (Δb*: -5.92%, P < 0.001), decreased skin autofluorescence (SAF: -14.23, P < 0.001), and received 97% participant satisfaction after 56 days. In conclusion, DEC effectively targets both oxidative stress and glycation pathways to inhibit melanogenesis, highlighting the potential of dual-targeting approaches in hyperpigmentation treatment.

Keywords:  Glycation; Hyperpigmentation; Melanogenesis; Oxidative stress; Skin lightness

DOI:  https://doi.org/10.1038/s41598-025-21315-9
J Mol Endocrinol. 2025 Oct 09. pii: JME-25-0081. [Epub ahead of print]

Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens.

Geovanni Alberto Ruiz-Romero, Johanna Bernáldez-Sarabia, Magdiel Orozco-Valdivia, Jessica Yazbel Romero-Rico, Pablo Garrido, Gonzalo Isaí Flores-Acosta, Alfredo Martínez, Carolina Álvarez-Delgado.

  Estrogens are steroid hormones that regulate antioxidant and mitochondrial bioenergetic metabolism in addition to activating nuclear genomic pathways. Concentrating these effects within the mitochondria is a novel strategy for ameliorating mitochondrial dysfunction, which is characteristic of cancer, metabolic, and neurodegenerative diseases. The use of synthetic mitochondria-targeted estrogens containing a triphenylphosphonium group may provide a basis for improving mitochondrial function in these conditions. Here, we evaluate the effects of two compounds, one derived from 17β-estradiol (mitoE2) and the other from 17α-ethinylestradiol (mitoEE2) on cell viability in MCF-7 and CCD-1112Sk cells. We further examine their influence on the activities of superoxide dismutase (MnSOD), citrate synthase (CS), cytochrome c oxidase (COX), and ATP synthase, as well as in the glycolytic reserve and cellular respiration. In both cellular models, cell viability assays indicated that MitoE2 was well tolerated below 500 nM, while MitoEE2 allowed treatments up to 100 nM for up to 24 hours. We found that the molecules act differently on enzymatic targets. Exposure of MCF-7 cells to mitoE2 resulted in reduced MnSOD activity. Pretreatment with MitoE2 or MitoEE2 restored the viability of MCF-7 cells exposed to H2O2-induced oxidative damage to levels comparable to untreated controls. Additionally, MitoEE2 increased the activities of CS and COX. Both mitochondria-targeted estrogens increased glycolytic reserve and mitochondrial respiration, as determined by extracellular flux assays. Overall, these findings suggest that the antioxidant and bioenergetic effects observed encourage further investigation into their potential as therapeutic strategies for conditions linked to mitochondrial dysfunction.

Keywords:  antioxidant effects; estrogens; mitochondria-targeted estrogens; mitochondrial metabolism; oxygen consumption rate

DOI:  https://doi.org/10.1530/JME-25-0081
Front Physiol. 2025 ;16 1606267

Resisting decline: the neuroprotective role of resistance exercise in supporting cerebrovascular function and brain health in aging.

Elric Y Allison, Anjali M Bedi, Aedan J Rourke, Vanessa Mizzi, Jeremy J Walsh, Jennifer J Heisz, Baraa K Al-Khazraji.

  Reduced cerebral blood flow (CBF) and cerebrovascular function are critical early-stage biomarkers preceding changes in brain function and structure observed in normal aging and during the onset and progression of Alzheimer's Disease and related dementias (ADRD). Though several interventions attempt to curb the effects of aging and brain neurodegeneration, exercise and lifestyle habits remain one of the most impactful and easily modifiable factors for preserving brain health. Although the effects of aerobic exercise on cerebrovascular function and brain health are well established, resistance training (RT) is rapidly increasing in popularity across all age demographics due to its numerous health benefits. Despite the clear physiological benefits of resistance exercise, its potential efficacy for preserving or improving cerebrovascular and overall brain health remains understudied to date. The aim of this review is to examine the literature pertaining to ways in which resistance exercise may reduce the risk of ADRD and slow age-related decline of brain structures and functions. Additionally, this review seeks to highlight key considerations and challenges regarding the feasibility, adoption, and adherence to resistance exercise in the context of normal aging, mild cognitive impairment, and ADRD.

Keywords:  Alzheimer’s disease related dementias; aging; brain health; cerebral blood flow (CBF); cerebrovascular; neurodegeneration; resistance exercise; resistance training (RT)

DOI:  https://doi.org/10.3389/fphys.2025.1606267
NPJ Metab Health Dis. 2024 May 27. 2(1): 6

Multifaceted mitochondria in innate immunity.

Eloïse Marques, Robbin Kramer, Dylan G Ryan.

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

DOI: https://doi.org/10.1038/s44324-024-00008-3