bims-mistre 2025-09-28 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–09–28
twenty papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.
Oxidative Stress, Advanced Glycation End Products (AGEs), and Neurodegeneration in Alzheimer's Disease: A Metabolic Perspective.
Mitochondria-driven inflammation: a new frontier in ovarian ageing.
Exploring ovarian aging: unraveling the link between mitochondria status and oocyte as a determinant of gamete quality.
A Multi-Ingredient Supplement Improves Body Re-Composition, Ovarian Aging Markers, and Reproductive Success in Young and Middle-Aged Female Mice.
Mitochondria, Sex, and Cardiovascular Disease: A Complex Interplay.
NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions.
Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
Antioxidant Effect of Curcumin and Its Impact on Mitochondria: Evidence from Biological Models.
Fluoxetine as an Antidepressant Agent Induces Directly Deleterious Effects on Rat Isolated Pancreatic Mitochondria: Ameliorative Role of Betanin.
Energy metabolism in different skeletal muscles and muscle fibers: implications for injury and dietary supplementation.
Cross-Organ Mitochondrial Communication in Stress and Disease.
Beyond Hot Flashes: The Role of Estrogen Receptors in Menopausal Mental Health and Cognitive Decline.
Loganin, an Iridoid Glycoside, Alleviates Paclitaxel-Induced Skeletal Muscle Toxicity by Enhancing Mitochondrial Function, Boosting Antioxidant Defenses, and Reducing Cellular Senescence.
A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.
Lactiplantibacillus plantarum HY7715 Alleviates Restraint Stress-Induced Anxiety-like Behaviors by Modulating Oxidative Stress, Apoptosis, and Mitochondrial Function.
A preliminary analysis of the relationship between follicle-stimulating hormone and metabolic parameters in postmenopausal women.
Hesperetin ameliorates mitochondrial dysfunction in acute kidney injury by mediating autophagy and inhibiting the cGAS-STING pathway.
Effects of 30-Day High-Dose Omega-3 Fatty Acid Supplementation on Plasma Oxidative Stress Enzyme Activities in Recreational and Trained Runners: A Pilot Study.
Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway.

Biomolecules. 2025 Aug 29. pii: 1252. [Epub ahead of print]15(9):

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease.

Davide Steffan, Camilla Pezzini, Martina Esposito, Anais Franco-Romero.

  Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration.

Keywords:  CNS; aging; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biom15091252
Antioxidants (Basel). 2025 Aug 25. pii: 1044. [Epub ahead of print]14(9):

Oxidative Stress, Advanced Glycation End Products (AGEs), and Neurodegeneration in Alzheimer's Disease: A Metabolic Perspective.

Virginia Boccardi, Francesca Mancinetti, Patrizia Mecocci.

  Neurodegenerative diseases such as Alzheimer's disease (AD) are closely linked to oxidative stress and advanced glycation end products (AGEs), two interrelated processes that exacerbate neuronal damage through mitochondrial dysfunction, protein aggregation, and chronic inflammation. This narrative review explores the metabolic interplay between reactive oxygen species (ROS) and AGEs, with a focus on the AGE-RAGE (receptor for advanced glycation end products) signaling axis as a driver of neurodegeneration. Evidence from preclinical and clinical studies highlights their combined role in disease progression and underscores potential therapeutic targets. Strategies including mitochondria-targeted antioxidants, AGE inhibitors, RAGE antagonists, and metabolic interventions are discussed, along with future directions for biomarker development and personalized treatments. This review integrates current molecular insights into a unified metabolic-inflammatory model of AD, highlighting translational therapeutic opportunities.

Keywords:  aging; inflammation; insulin; metabolism; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3390/antiox14091044
J Transl Med. 2025 Sep 24. 23(1): 1005

Mitochondria-driven inflammation: a new frontier in ovarian ageing.

Wenhan Ju, Binghan Yan, Danping Li, Fang Lian, Shan Xiang.

  Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation. Furthermore, an imbalance in mitochondrial quality control mechanisms can worsen the spread and persistence of inflammatory responses. In this study, we present a comprehensive overview of the signalling origins, molecular mechanisms of amplification, and key regulatory nodes involved in mitochondria-driven inflammation during ovarian ageing. Finally, we summarise potential therapeutic strategies targeting mitochondria-driven inflammation, offering novel perspectives and targets for delaying ovarian ageing and enhancing female reproductive health.

Keywords:  Damage-associated molecular patterns; Inflammation; Mitochondria; Mitochondrial dysfunction; Ovarian ageing

DOI:  https://doi.org/10.1186/s12967-025-06966-6
Syst Biol Reprod Med. 2025 Dec;71(1): 461-484

Exploring ovarian aging: unraveling the link between mitochondria status and oocyte as a determinant of gamete quality.

Manuel Belli, Marta Gatti, Luigi Sansone, Matteo Antonio Russo, Maria Grazia Palmerini, Stefania Annarita Nottola, Mohammad Ali Khalili, Guido Macchiarelli.

  The variation in reproductive age among individuals is significant, with many cases of infertility involving premature ovarian aging. This issue, combined with the societal trend of delaying childbearing, leads to age-related ovarian dysfunction. Ovarian aging is related to a decline of ovarian reserve, as oocyte quantity, quality, and precocious senescence, and may affect fertility and the overall individual well-being. Mitochondria play a central role in the maintenance of any cell health. Then mitochondrial dysfunctions may be responsible also for a negative impact on the quality, number, and function of oocytes, leading to different age-related reproductive disorders, impaired oogenesis, and embryogenesis. Although a large number of researches have shown clearly that mitochondrial dysfunction and morphology changes affect the maintenance and function of all major organs and tissues, such as the brain, heart, skeletal muscle, liver, and others the mechanisms contributing to early ovarian aging, a decrease of oocyte quality, and infertility remain unclear. In this review, we summarize the role of mitochondrial dysfunction in ovarian aging, presenting recent findings on morpho-functional changes in these organelles, and highlighting how their dysfunction accelerates ovary and cell senescence. We also explore their impact on oocyte functions. The reported data highlight the critical role of mitochondria in maintaining and enhancing oocyte quality, indicating that future studies should further focus on the mechanisms underlying mitochondrial damage and on identifying mitochondrial targets that may offer promising strategies to preserve, recover, and extend fertility in aging women.

Keywords:  Molecular and cellular fertility rehabilitation; functional recovery from infertility; mitochondria; oocyte; ovarian aging

DOI:  https://doi.org/10.1080/19396368.2025.2562633
Biomolecules. 2025 Aug 30. pii: 1258. [Epub ahead of print]15(9):

A Multi-Ingredient Supplement Improves Body Re-Composition, Ovarian Aging Markers, and Reproductive Success in Young and Middle-Aged Female Mice.

Alessandra Chiarot, Mahek Minhas, Nicoletta M de Maat, Jenny Doan, Mats I Nilsson, Bart P Hettinga, Mehrnoosh Faghih, Michael S Neal, Joshua P Nederveen, Mark A Tarnopolsky.

  Ovarian aging is characterized by mitochondrial dysfunction, oxidative stress, and inflammation. The development of adjunctive treatments that mitigate age-related subfertility is warranted. We examined the benefits of nutraceutical supplementation (FE; Fertility Enhancer) with mitochondrial antioxidants, anti-inflammatory agents, metabolic activators, vitamins and minerals, and amino acids on ovarian aging, metabolic activity, and reproductive success in young (Y; 6-month-old) and middle-aged (O; 11-month-old) female C57BL/6J mice. The mice were fed calorie- and macronutrient-matched diets w/wo the FE supplement for three months and harem mated twice. Daily FE supplementation promoted significant body re-composition, including loss of white adipose tissue (gWAT: -36% vs. CON, p < 0.001), gain of skeletal muscle (SkM: +67% vs. CON, p < 0.001), and improved SkM/gWAT ratio (+185% vs. CON, p < 0.001). Metabolic testing showed enhanced fat oxidation (+38%, p < 0.01) and energy expenditure (+7%, p = 0.051) in FE mice. Breeding and immunoblotting data demonstrated improved reproductive success (Y-CON: 44%, Y-FE: 89%, O-CON: 0%, O-FE: 18%) and a modest attenuation of ovarian aging markers in both FE groups. We surmise that a multi-ingredient supplement, such as the Fertility Enhancer, may improve body re-composition, metabolic activity, and markers of ovarian aging, thus enhancing reproductive health and fertility in females.

Keywords:  aging; antioxidants; fat; fertility; inflammation; mitochondria; muscle; nutraceuticals; obesity; oxidative stress

DOI:  https://doi.org/10.3390/biom15091258
Int J Mol Sci. 2025 Sep 15. pii: 8971. [Epub ahead of print]26(18):

Mitochondria, Sex, and Cardiovascular Disease: A Complex Interplay.

Andrea Iboleon-Jimenez, Alberto Contreras-Muñoz, Cristian Peláez-Berdún, Rafael Franco-Hita, Alba Sesmero, Ainhoa Robles-Mezcua, Jose M García-Pinilla, Manuel Jimenez-Navarro, Mora Murri.

  Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. Increasing evidence indicates that sex differences significantly influence the development, progression, and outcomes of CVDs. Recent advances have highlighted the central role of mitochondria, not only as cellular energy hubs but also as key regulators of oxidative stress, inflammation, and apoptosis, in mediating sex-specific cardiovascular responses. This review explores sexual dimorphism in cardiovascular disease, focusing on the interplay between mitochondrial function and sex hormones in cardiovascular tissues. We summarize current evidence on the molecular, hormonal, and cellular mechanisms contributing to sex-based disparities in cardiovascular outcomes. Preclinical studies suggest that female cardiac mitochondria may exhibit greater antioxidant capacity and produce fewer reactive oxygen species than male mitochondria, contributing to enhanced cardioprotection. Estrogen has been shown to influence mitochondrial bioenergetics and gene expression, affecting vascular tone, inflammation, and cardiac remodelling, whereas the role of testosterone remains less well defined. Additionally, sex-specific mitochondrial signalling responses have been reported under cardiac stress conditions, which may underlie differences in disease presentation and progression. A better understanding of how sex modulates mitochondrial function could improve risk stratification and support the development of personalized prevention and treatment strategies. Further research is needed to translate these mechanistic insights into clinical practice.

Keywords:  cardiovascular diseases; mitochondria; mitochondrial dysfunction; sex; sex dimorphism

DOI:  https://doi.org/10.3390/ijms26188971
Reprod Toxicol. 2025 Sep 19. pii: S0890-6238(25)00238-2. [Epub ahead of print] 109067

NAD+ precursors mitigate the in vitro and in vivo reproductive defects: Limitations and possible solutions.

Nazli Pinar Arslan, Zuleyha Akpinar, Havva Aybek, Meryem Doymus, Gulsum Asilkan-Kaldik, Nevzat Esim, Mesut Taskin.

  In mammalian cells, nicotinamide adenine dinucleotide (NAD+) participates in the regulation of diverse cellular processes such as ATP production, oxidative stress resistance, DNA repair, metabolic homeostasis, and inflammation. Due to these properties, exogenously applied NAD+ precursors (nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide) can protect organs and cells of mammalian against detrimental effects of various stress factors and diseases. For instance, NAD+ and its precursors have critical importance for the in vivo and in vitro fertilization success of mammals. This review summarizes that the natural aging process, diseases, and toxic compounds cause the detrimental effects in the reproductive parameters of the in vivo models, such as the meiotic defects and the reductions in cellular NAD+ level, mitochondrial functions, sperm and oocyte quality, blastocyst and embryo formation rate, implantation success, whereas the intragastric, intraperitoneal or oral administration of NAD+ precursors prevents or attenuates these detrimental effects. Similarly, the supplementation of NAD+ precursors can protect the oocytes and sperms against the cryopreservation process, aging and toxic compounds in the in vitro and also enhances blastocyst and embryo formation in vitro. This review study also revealed that the ability of NAD+ precursors-loaded drug delivery systems to prevent reproductive defects has not yet been investigated in literature. Therefore, we recommend the development of NAD+ precursor-loaded drug delivery systems targeting reproductive system organs and/or cell organelles (mitochondria, endoplasmic reticulum and nucleus). To achieve this, hormone receptors in testicular and ovarian cells can be targeted. Similarly, triphenylphosphonium (TPP+) can be used to specifically target mitochondria.

Keywords:  NAD(+) precursors; assisted reproductive technology; drug delivery; infertility; oxidative stress; sirtuins

DOI:  https://doi.org/10.1016/j.reprotox.2025.109067
Nat Cardiovasc Res. 2025 Sep 24.

Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.

Sumeet A Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L Smythers, Katherine A Blackmore, Louisa Grauvogel, Melanie J Mittenbühler, Melin J Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E Houstis, Hans-Georg Sprenger, Sean J Jurgens, Kiran J Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T Ellinor, Matthias Nahrendorf, Joao A Paulo, Steven P Gygi, Phillip A Dumesic, Aarti Asnani, Krishna G Aragam, Pere Puigserver, Jason D Roh, Bruce M Spiegelman, Anthony Rosenzweig.

Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.

DOI: https://doi.org/10.1038/s44161-025-00712-3
J Xenobiot. 2025 Aug 31. pii: 139. [Epub ahead of print]15(5):

Antioxidant Effect of Curcumin and Its Impact on Mitochondria: Evidence from Biological Models.

Karla Alejandra Avendaño-Briseño, Jorge Escutia-Martínez, Estefani Yaquelin Hernández-Cruz, José Pedraza-Chaverri.

  Curcumin, the principal active component of turmeric, is a polyphenol that has been used in various countries for the treatment of numerous conditions due to its wide range of health benefits. Curcumin exhibits bifunctional antioxidant properties: the first is attributed to its chemical structure, which enables it to directly neutralize reactive oxygen species (ROS); the second is related to its ability to induce the expression of antioxidant enzymes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Both ROS and Nrf2 are closely associated with mitochondrial function and metabolism, and their dysregulation may lead to mitochondrial dysfunction, potentially contributing to the development of various pathological conditions. Therefore, curcumin treatment appears highly promising and is strongly associated with the preservation of mitochondrial function. The aim of this review is to summarize the current literature on the impact of curcumin's antioxidant properties on mitochondrial function. Specifically, studies conducted in different biological models are included, with emphasis on aspects such as mitochondrial respiration, antioxidant enzyme activity, interactions with mitochondrial membranes, and the role of curcumin in the regulation of intrinsic apoptosis.

Keywords:  antioxidants; curcumin; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.3390/jox15050139
Xenobiotica. 2025 Sep 23. 1-30

Fluoxetine as an Antidepressant Agent Induces Directly Deleterious Effects on Rat Isolated Pancreatic Mitochondria: Ameliorative Role of Betanin.

Ahmad Salimi, Saleh Khezri, Amir Mohsen Azami, Samin Tayefeh Ayremlou, Vahed Adhami.

  1.It has been shown that fluoxetine is cytotoxic on pancreatic beta-cells via induction of mitochondrial dysfunction and oxidative stress. We investigated the direct effect of fluoxetine on isolated pancreatic mitochondria and evaluate the potential protective effects of betanin and thymoquinone.2. Mitochondria were isolated from rat pancreas and treated with various concentrations of fluoxetine (10-8000 µM). Then, protective effect of betanin (100-500 µM) and thymoquinone (10-100 µM) on fluoxetine-induced mitochondrial toxicity were studied (60 min). The activity of succinate dehydrogenases (SDH), reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, malondialdehyde (MDA) production and glutathione level were analyzed.3. Fluoxetine directly caused toxicity in pancreatic isolated mitochondria at concentration of 500 μM and higher. Except MDA and GSH, fluoxetine caused significantly SDH activity reduction, MMP collapse, mitochondrial swelling and ROS formation in pancreatic mitochondria. However, our results showed that only betanin protected fluoxetine-induced mitochondrial dysfunction, while thymoquinone had no impact on mitochondrial toxicity induced by fluoxetine.4. We can conclude that fluoxetine is directly toxic on pancreas isolated mitochondria, which may be related to its diabetogenic potential in humans. Moreover, our finding suggested that use of betanin may be beneficial for prevention of diabetogenic effect of fluoxetine.

Keywords:  Betanin; Diabetes; Fluoxetine; Mitochondria; Pancreatic Beta-Cells; Thymoquinone

DOI:  https://doi.org/10.1080/00498254.2025.2564120
Pflugers Arch. 2025 Sep 27.

Energy metabolism in different skeletal muscles and muscle fibers: implications for injury and dietary supplementation.

Andrey V Kuznetsov, Raimund Margreiter, Judith Hagenbuchner, Michael J Ausserlechner.

  The necessary energy supply in skeletal muscles is based on either glycolysis or mitochondrial oxidative phosphorylation (OxPhos). These two bioenergetic pathways are in balanced complementation. Glycolysis is faster than OxPhos, whereas OxPhos is much more efficient. One common feature of both pathways is the compartmentation of high-energy phosphates and their metabolic channeling. The glycolytic muscles are wider, whereas oxidative muscles have significantly more mitochondria. Importantly, a striking difference in bioenergetic mechanisms in oxidative (slow-twitch) versus glycolytic (fast-twitch) muscles and muscle fibers has been clearly shown. The advantage is that the optimal fiber diversity can provide the best muscle function. Various creatine kinase isoforms and phosphocreatine play an important role in glycolytic and oxidative muscles energy metabolism, but their roles are very different, depending on the muscle type. In the glycolytic muscles, phosphocreatine, produced from creatine and ATP by cytosolic creatine kinase, is mostly considered a cellular energy store for fast ATP delivery, whereas in the oxidative muscles, phosphocreatine and mitochondrial creatine kinase are the main players in the intracellular energy transport.

Keywords:  Bioenergetics; Cardiac/skeletal muscles energy metabolism; Creatine/phosphocreatine; Intracellular energy transport; Mitochondria; Mitochondrial ROS

DOI:  https://doi.org/10.1007/s00424-025-03112-5
Annu Rev Pharmacol Toxicol. 2025 Sep 22.

Cross-Organ Mitochondrial Communication in Stress and Disease.

Koning Shen, Jenni Durieux, Andrew Dillin.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1146/annurev-pharmtox-062124-024150
Brain Sci. 2025 Sep 16. pii: 1003. [Epub ahead of print]15(9):

Beyond Hot Flashes: The Role of Estrogen Receptors in Menopausal Mental Health and Cognitive Decline.

Jung Min Cho, Jihye Lee, Eun-Mi Ahn, Jaehoon Bae.

  Menopause is a natural phase in a woman's life marked by the cessation of menstruation, typically accompanied by hormonal fluctuations that have significant impacts on physical and mental health. While much attention has been given to the physical symptoms of menopause, such as hot flashes and osteoporosis, the neurocognitive consequences of hormonal fluctuations during the menopausal transition and the subsequent sustained estrogen loss after menopause have received less focus. Estrogen receptors (ERs), specifically ERα and ERβ, play a critical role in maintaining brain health, influencing mood, memory, and cognition. This review explores the connection between estrogen receptor signaling and mental health during menopause, focusing on mood disorders such as depression and anxiety, as well as cognitive decline and dementia. We discuss the molecular mechanisms by which ERs modulate brain function, including their effects on neuroplasticity, neurotransmitter systems, and gene expression. The review also examines current clinical approaches to managing menopausal cognitive and mental health issues, including hormone replacement therapy and selective ER modulators, while emphasizing the need for further research into alternative therapies and individualized treatments. The importance of estrogen receptors in the menopausal brain and their potential as therapeutic targets is critically evaluated, aiming to shed light on this often-overlooked aspect of menopause and aging.

Keywords:  cognitive decline; estrogen receptors; menopause; mental health; neuroprotection

DOI:  https://doi.org/10.3390/brainsci15091003
Kaohsiung J Med Sci. 2025 Sep 27. e70117

Loganin, an Iridoid Glycoside, Alleviates Paclitaxel-Induced Skeletal Muscle Toxicity by Enhancing Mitochondrial Function, Boosting Antioxidant Defenses, and Reducing Cellular Senescence.

Yu-Fan Chuang, Cai-Rong Wu, Wan-Hsuan Chang, Ying-Jung Su, Hung-Te Hsu, Fan-Li Lin, Yi-Ching Lo.

  Mitochondrial dysfunction and energy imbalance caused by chemotherapy are key contributors to skeletal muscle atrophy, which severely impacts the quality of life in cancer patients. Paclitaxel, a commonly used chemotherapeutic agent, is known to promote muscle wasting and cellular senescence, largely by impairing mitochondrial function. In this study, we investigated the protective role of loganin, a naturally occurring iridoid glycoside, in preventing paclitaxel-induced damage to skeletal muscle cells. Using C2C12 cells, we assessed whether loganin could counteract the harmful effects of paclitaxel. Our results demonstrated that loganin significantly improved cell viability and protected mitochondrial function, as reflected by better preservation of mitochondrial DNA content, membrane potential, and ATP production, while further enhancing mitochondrial biogenesis through upregulation of PGC-1α, TFAM, and NRF1. In parallel, loganin activated metabolic regulators SIRT1 and AMPK, while restoring PDK4 expression, suggesting improved energy regulation. Additionally, glycogen levels and myotube morphology were maintained, alongside sustained myosin heavy chain expression. Loganin effectively reduced both cellular and mitochondrial reactive oxygen species and increased antioxidant defenses, including superoxide dismutase activity and glutathione levels. Notably, it also suppressed paclitaxel-induced senescence and inflammation, as shown by decreased p21 expression, reduced NFκB phosphorylation, and lower levels of Cdkn1a and Il6 as well as reduced SA-β-gal staining. Overall, our findings demonstrate that loganin offers comprehensive protection against paclitaxel-induced skeletal muscle injury by preserving mitochondrial function, supporting metabolic homeostasis, reducing oxidative stress, and limiting senescence. These results highlight the potential of loganin as a preventive adjunctive agent to mitigate chemotherapy-related muscle toxicity.

Keywords:  cellular senescence; loganin; mitochondrial dysfunction; paclitaxel‐induced myotoxicity; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/kjm2.70117
Signal Transduct Target Ther. 2025 Sep 26. 10(1): 315

A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics.

Zhiheng Rao, Zhichao Chen, Yuxuan Bao, Zhenzhen Lu, Yuli Tang, Jiamei Zhu, Jianjia Ma, Siyang Dong, Jiawei Shi, Suhui Sheng, Yajing Chen, Jiaojiao Wang, Alan Vengai Mukondiwa, Ziyue Li, Xulan Wang, Zibo Huang, Chi Li, Wumengwei Ding, Mengjie Chen, Ziyi Han, Cong Wang, Xuebo Pan, Xiaojie Wang, Hong Zhu, Li Lin, Zhifeng Huang, Weiqin Lu, Xiaokun Li, Yongde Luo.

The heart, an organ with a continuously high demand for energy, inherently lacks substantial reserves. The precise mechanisms that prioritize energy allocation to cardiac mitochondria, ensuring steady-state ATP production amidst high-energy organs, remain poorly understood. Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21. We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux, arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency, directly impair cardiac energetic performance. Locally, this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways, along with hindered mitochondrial biogenesis, TCA cycle, ETC flow, and OXPHOS. Consequently, the heart shifts to a hypometabolic, glycolytic, and hypoenergy state, with a reduced capacity to cope with physiological stressors such as fasting, starvation, strenuous exercise, endurance training, and cold exposure, leading to a diminished heart rate, contractility, and hemodynamic stability. Pharmacological or genetic restoration of FGF21 ameliorates these defects, reenergizing stress-exhausted hearts. This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways. Disrupting cardiac LKB1 or mTOR pathways, akin to stalling mitochondrial energy conduits, obstructs the FGF21-governed cardiac energetic potential. Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21, which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency. This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.

DOI: https://doi.org/10.1038/s41392-025-02402-9
Int J Mol Sci. 2025 Sep 22. pii: 9251. [Epub ahead of print]26(18):

Lactiplantibacillus plantarum HY7715 Alleviates Restraint Stress-Induced Anxiety-like Behaviors by Modulating Oxidative Stress, Apoptosis, and Mitochondrial Function.

Kippuem Lee, Daehyeop Lee, Haeryn Jeong, Joo Yun Kim, Jae Jung Shim, Jae Hwan Lee.

  Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 109 CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders.

Keywords:  Lactiplantibacillus plantarum HY7715; anxiety; neuroprotection; psychobiotics

DOI:  https://doi.org/10.3390/ijms26189251
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2562195

A preliminary analysis of the relationship between follicle-stimulating hormone and metabolic parameters in postmenopausal women.

Federica Barbagallo, Agata Cavallaro, Rossella Cannarella, Andrea Crafa, Rosita A Condorelli, Sandro La Vignera, Laura Cucinella, Rossella E Nappi, Aldo E Calogero.

  After menopause, women have a higher risk of developing metabolic disorders. The discovery of follicle-stimulating hormone (FSH) receptors in extra-ovarian tissues such as the adipose tissue suggests that FSH might influence metabolic processes in postmenopausal women. However, its role remains unclear. To examine the association between serum FSH levels and glucose and lipid metabolism in postmenopausal women. A retrospective analysis was conducted on 82 postmenopausal women (mean age 65.2 ± 8.1 years). Serum levels of FSH, 17β-estradiol (E2), glucose, insulin, HbA1c, total cholesterol, LDL, HDL, and triglycerides were measured. Insulin resistance was calculated using the HOMA-IR index. FSH levels did not significantly differ between women with and without dyslipidemia. However, FSH levels were significantly lower in women with type 2 diabetes (44.3 ± 13.8 IU/mL) compared to those with insulin resistance (60.6 ± 29.4 IU/mL) or normal glucose metabolism (69.4 ± 27.2 IU/mL; p = 0.045). Women in the lowest FSH quartile had higher glucose, insulin, and HOMA-IR values. A significant inverse correlation between FSH and insulin (r = -0.30, p = 0.03) was found, stronger in women more than six years postmenopausal. Serum FSH levels inversely correlate with glucose metabolism disorders in postmenopausal women. These findings suggest a possible role of FSH in glucose metabolism, deserving further study starting from the menopausal transition.

Keywords:  Menopause; adipose tissue; central obesity; dyslipidemia; follicle-stimulating hormone; insulin resistance; metabolic syndrome; metabolism

DOI:  https://doi.org/10.1080/09513590.2025.2562195
J Mol Histol. 2025 Sep 27. 56(5): 330

Hesperetin ameliorates mitochondrial dysfunction in acute kidney injury by mediating autophagy and inhibiting the cGAS-STING pathway.

Pei Cao, Wan Zhu, Deng Li, JiGang Zhang, Xing Feng.

  Cisplatin-induced acute kidney injury (AKI) represents a severe complication of anticancer therapy with no effective clinical interventions, frequently necessitating chemotherapy dose reduction or discontinuation. Natural products have emerged as promising therapeutic candidates against cisplatin nephrotoxicity due to their multi-target mechanisms, pleiotropic effects, and low resistance potential. This study explored the therapeutic potential of hesperetin (Hes) in ameliorating mitochondrial dysfunction during AKI through coordinated induction of autophagy and suppression of the cGAS-STING pathway. We established an HK-2 cell injury model through cisplatin exposure. Following Hes intervention, cell viability was quantified via CCK-8 assays, apoptosis assessed by Annexin V-FITC/PI staining, and mitochondrial function evaluated through ATP production measurement, mitochondrial reactive oxygen species (ROS) detection and mitochondrial membrane potential analysis employing JC-1 staining. For in vivo validation, C57BL/6 mice developed AKI following single intraperitoneal cisplatin administration. Renal function parameters were determined through serum biochemistry, while renal histopathology was examined using periodic acid-Schiff (PAS) staining. Protein expression changes in mitochondrial autophagy markers and cGAS-STING pathway components were subsequently analyzed through immunofluorescence and Western blotting techniques. Autophagy modulators were employed to elucidate the precise mechanisms through which autophagy mediates Hes's protective effects against cisplatin-induced AKI. In vitro, Hes intervention effectively reversed cisplatin-induced HK-2 cell injury and mitochondrial dysfunction while enhancing mitochondrial autophagy. Notably, the autophagy activator rapamycin alone, or co-administered with Hes produced comparable cytoprotective effects to Hes. Conversely, the autophagy inhibitor 3-methyladenine exacerbated cellular damage and partially attenuated Hes-mediated protection. In vivo studies confirmed Hes significantly ameliorated AKI through improved renal function and histopathology, concurrently reducing mitochondrial ROS levels while promoting autophagic clearance. Furthermore, Hes treatment potently suppressed activation of the cGAS-STING pathway in both experimental models. Hes ameliorates mitochondrial dysfunction in AKI by enhancing mitochondrial autophagy and inhibiting the cGAS-STING pathway.

Keywords:  Autophagy; HK-2 cells; Hesperetin; Mitochondrial dysfunction; cGAS-STING

DOI:  https://doi.org/10.1007/s10735-025-10602-4
Nutrients. 2025 Sep 17. pii: 2985. [Epub ahead of print]17(18):

Effects of 30-Day High-Dose Omega-3 Fatty Acid Supplementation on Plasma Oxidative Stress Enzyme Activities in Recreational and Trained Runners: A Pilot Study.

Bojan Martinšek, Milan Skitek, Tina Kosjek, Leon Bedrač, Evgen Benedik.

  Background: Physical activity induces the production of reactive oxygen species (ROS), which, at moderate levels mediate beneficial physiological adaptations, including insulin sensitivity and enhanced antioxidant defense. However, excessive ROS production during intense exercise may exceed endogenous antioxidant capacity, leading to oxidative stress and muscle damage. Objective: This study examined the effects of 30-day high-dose omega-3 fatty acid supplementation (9 g/day) on plasma fatty acid composition and the activity of antioxidant enzymes in recreational (n = 11) and trained (n = 10) runners, with emphasis on group- and time-specific responses. Methods: Plasma levels of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were assessed at three time points: pre-, during, and post-supplementation period. Enzymatic activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were measured at six time points, including before and after exercise sessions involving a 2800 m run followed by a 400 m sprint. Results: Omega-3 supplementation increased plasma EPA and DHA. In trained runners, it was associated with a transient reduction in GPx and a pronounced mid-phase decline in SOD, whereas enzyme activities remained stable in recreational runners. CAT activity did not change significantly in either group. Conclusions: Short-term high-dose omega-3 supplementation modulates antioxidant enzyme activity in a group- and time-dependent manner. The observed downregulation of GPx and SOD in trained runners may reflect altered redox signaling; however, its relevance for exercise performance remains uncertain. Further studies are warranted to elucidate the physiological and functional consequences of these findings.

Keywords:  catalase; glutathione peroxidase; omega-3; physical activity; polyunsaturated fatty acids; reactive oxygen species; running; superoxide dismutase

DOI:  https://doi.org/10.3390/nu17182985
Drug Dev Res. 2025 Nov;86(7): e70171

Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway.

Hao Ling, Chunli Song.

  ‌Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0-200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA (p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.

Keywords:  mitochondrial damage; mitophagy; oleuropein; oxidative stress

DOI:  https://doi.org/10.1002/ddr.70171