bims-mistre 2025-08-31 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–08–31
thirty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.
The role of mitochondrial function in the pathogenesis of diabetes.
Evolutionary diversity of muscle OXPHOS efficiency in vitro across ectothermic vertebrates.
Roles of SIRT3 in aging and aging-related diseases.
Downregulation of microRNA-494 drives mitochondrial biogenesis and function in trained muscle.
Critical Review on Molecular Mechanisms for Genistein's Beneficial Effects on Health Through Oxidative Stress Reduction.
Mitochondrial Dysfunction and Oxidative Stress: Emerging Insights in Muscle and Cardiovascular Disease Mechanisms.
Sex steroid hormones drive dimorphic responses in GDF15-deficient mouse models of cardiometabolic diseases.
Camellia japonica Flower Extract and the Active Constituent Hyperoside Repair DNA Damage Through FUNDC1-Mediated Mitophagy Pathway for Skin Anti-Aging.
Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.
Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.
Emerging Roles of GDF15 in Metabolic and Cardiovascular Diseases.
MitoQ alleviates malathion‑induced hepatorenal toxicity via oxidative stress and inflammation modulation.
Liquiritigenin Restores Declined Oocyte Quality and Improves Embryo Development in Aged Mice.
Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.
Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.
Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer's disease.
EGCG and Taurine Synergistically Ameliorate Lipid Metabolism Disorder by Modulating Gut Microbiota and PPARα/FAS Signaling Pathway.
Zuogui and Yougui pills extend lifespan and improve ageing biomarkers via kaempferol-mediated mitophagy in Caenorhabditis elegans.
Endothelial mitochondria in the blood-brain barrier.
Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.
Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging.
The Final Phases of Ovarian Aging: A Tale of Diverging Functional Trajectories.
Is mitochondrial function at the heart of ribosome-related diseases?
Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging.
Mild Mitochondrial Uncoupling for True Ectopic Lipid Disposal.
Epigallocatechin gallate-mediated inhibition of mitochondrial DNA sensing regulated by TBK1/cGAS/STING and NLRP3 alleviates cardiovascular toxicity in atherosclerosis.
Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.
Systems and Molecular Biology of Longevity and Preventive Medicine: Brain-Energy-Microbiome-Exposome Synergies in Blue Zones and the Cilento Case.
Modulation of Aging Diseases via RAGE Targets: A Dietary Intervention Review.
Mitochondrial Reactive Oxygen Species Production in Vascular Dementia Following Experimental Diabetes.

Inflammopharmacology. 2025 Aug 27.

Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.

Rufaida Wasim.

  The pathophysiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, is greatly impacted by mitochondrial dysfunction. Recent research suggests that a number of interconnected processes, such as elevated oxidative stress, disturbed energy metabolism, compromised calcium homeostasis, and malformed mitochondrial dynamics, all lead to neuronal injury. The mitochondria in AD brains have structural defects and the function of important oxidative phosphorylation-related enzymes is lowered, which results in less ATP being produced. Further exacerbated by mitochondrial dysfunction is the build-up of amyloid-beta (Aβ) peptides and hyperphosphorylated tau proteins, which interact directly with mitochondrial membranes and proteins to cause mitochondrial fragmentation and hinder mitochondrial transport along neuronal axons. These occurrences cause an increase in reactive oxygen species (ROS) generation, which exacerbates oxidative damage and feeds a vicious cycle. In AD, mutations in mitochondrial DNA (mtDNA) and changes in mitochondrial biogenesis have also been documented, indicating a key involvement in the development of the illness. Preclinical models show promise for therapeutic approaches that attempt to maintain mitochondrial function, including antioxidants, drugs that target the mitochondria. It is crucial to comprehend the intricate relationship between mitochondrial dysfunction and other pathological aspects of AD to find new treatment targets and enhance patient outcomes. In addition to underlining its role in the development of AD, this review examines the complex interaction between mitochondrial dysfunction and AD pathogenesis, taking into account its potential as a biomarker and a target for intervention.

Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Oxidative stress; Pathology

DOI:  https://doi.org/10.1007/s10787-025-01916-6
Front Endocrinol (Lausanne). 2025 ;16 1607641

The role of mitochondrial function in the pathogenesis of diabetes.

Bo Qin, Yiying Wang, Jinlong Ding.

  Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated blood sugar levels due to insulin deficiency or insulin resistance, ultimately leading to various serious complications. In this review, we highlighted the significance of mitochondrial functionality in diabetes, concentrating on elements such as mitochondrial energy metabolism, oxidative stress, and their interplay with insulin sensitivity. Mitochondria are essential organelles that are crucial for energy production and integral to cellular metabolic processes. Recent investigations have underscored the role of mitochondrial dysfunction in the advancement of diabetes, uncovering fundamental mechanisms that lead to insulin resistance and elevated blood glucose levels. Present study amalgamates insights from contemporary studies, emphasizing the criticality of mitochondrial integrity in the occurrence of diabetes and its promise as a target for therapeutic intervention. By clarifying these associations, we aspire to offer novel perspectives and pathways for the prevention and management of diabetes.

Keywords:  diabetes mellitus (DM); energy metabolism (EM); insulin sensitivity (IS); mitochondrial function (MF); oxidative stress (OS)

DOI:  https://doi.org/10.3389/fendo.2025.1607641
Proc Biol Sci. 2025 Aug;292(2053): 20250374

Evolutionary diversity of muscle OXPHOS efficiency in vitro across ectothermic vertebrates.

Rachel Lockridge Mueller, Lance C Li Puma, Michael W Itgen, Adam J Chicco.

  Oxidative metabolism meets the majority of vertebrate energy demands through the coupling of mitochondrial respiration to ATP production (OXPHOS). In endotherms, variations in OXPHOS coupling efficiency influence metabolic thermogenesis, locomotor economy and reactive oxygen species (ROS) generation. However, the extent of these variations and their functional implications in ectotherms are less clear. We measured mitochondrial oxygen consumption, ATP production and ROS production in permeabilized skeletal muscle fibres from salamanders, frogs and lizards representing ectotherm clades with low, medium and high standard metabolic rates (SMRs), respectively. Consistent with predicted associations with SMR, lizards had the highest capacities for muscle mitochondrial ATP production, while salamanders had the lowest. Unexpectedly, corresponding rates of oxygen consumption followed an opposite trend, reflecting 8.5-fold variations in OXPHOS coupling efficiency between salamanders (the lowest) and lizards (the highest). Intrinsic proton permeability of the inner mitochondrial membrane was the primary source of OXPHOS coupling variation across species, being highest in salamanders and lowest in lizards. Basal proton leak mediated by uncoupling proteins and the adenine nucleotide translocase was only seen in lizards, where it limits mitochondrial ROS production. We infer that diverse evolutionary selection pressures drive unexpectedly wide variations in muscle OXPHOS efficiency with different functional implications across ectotherm clades.

Keywords:  bioenergetics; high-resolution respirometry; mitochondria; oxidative phosphorylation; standard metabolic rate; vertebrates

DOI:  https://doi.org/10.1098/rspb.2025.0374
Int J Biol Sci. 2025 ;21(11): 5135-5163

Roles of SIRT3 in aging and aging-related diseases.

Yuzi You, Zhong Wang.

  Aging is an inexorable pathophysiological progression characterized by the overwhelming deterioration of tissue integrity and cellular function coupled with increased risks of various aging-related diseases. Demographic shifts toward extended longevity have precipitated a paradigm shift in disease epidemiology, in which neurodegenerative conditions and cardiovascular pathologies now constitute predominant determinants of morbidity and mortality in geriatric populations. These conditions severely erode functional autonomy in aging populations and strain healthcare infrastructures globally. As a principal nicotine adenine dinucleotide-dependent deacetylase within mitochondria, sirtuin 3 (SIRT3) exerts multimodal regulatory effects spanning mitochondrial bioenergetics, oxidative stress, and epigenetic modifications associated with aging. This review summarizes recent discoveries regarding the involvement of SIRT3 in physiological aging and its pathophysiological intersections with major aging-related disorders, providing new insights and ample inspiration for future research aimed at slowing the aging process and improving outcomes in aging-related diseases.

Keywords:  Aging; Aging-related Diseases; Mitochondria; Neurodegenerative Diseases; SITR3

DOI:  https://doi.org/10.7150/ijbs.115518
Exp Physiol. 2025 Aug 25.

Downregulation of microRNA-494 drives mitochondrial biogenesis and function in trained muscle.

Natália Pálešová, Klára Gabrišová, Jana Babulicová, Patrik Krumpolec, Zuzana Kovaničová, Tímea Kurdiová, Salvatore Modica, Christian Wolfrum, Jozef Ukropec, Barbara Ukropcová, Miroslav Baláž.

  MicroRNAs (miRNAs) are key regulators of cellular processes, including mitochondrial function and energy metabolism. This study explores the regulation of miR-494 in skeletal muscle and circulation, investigating its response to exercise training and an acute exercise bout, its association with metabolic disorders, and the effects of electrical pulse stimulation (EPS). In addition, it validates the gene targets and physiological role of miR-494 using gain- and loss-of-function studies in primary human skeletal muscle cells. We demonstrate that miR-494 levels in both skeletal muscle and circulation are influenced by long-term exercise training, which induces adaptive changes, but remain unaffected by an acute bout of exercise. EPS does not alter miR-494 levels in cultured primary human skeletal muscle cells. Moreover, muscle miR-494 levels remain unchanged under various metabolic challenges, including obesity and type 2 diabetes. Genetic manipulation of miR-494 in primary human skeletal muscle cells modulates mitochondrial biogenesis and function, as well as lipid metabolism, through targeting PGC1A and SIRT1. Injection of a miR-494 inhibitor into skeletal muscle of mice supports the role of miR-494 in regulating Pgc1α mRNA, suggesting potential therapeutic implications. These findings highlight miR-494 as a significant modulator of mitochondrial dynamics and energy metabolism in skeletal muscle.

Keywords:  exercise; metabolism; microR‐494; mitochondria; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.1113/EP092977
Antioxidants (Basel). 2025 Jul 24. pii: 904. [Epub ahead of print]14(8):

Critical Review on Molecular Mechanisms for Genistein's Beneficial Effects on Health Through Oxidative Stress Reduction.

Ke Zhang, Jingwen Wang, Baojun Xu.

  Oxidative stress directly or indirectly contributes to the development and progression of various diseases; therefore, regulating oxidative stress is a promising strategy for preventing or treating these conditions. The unique substances in soybeans, soy isoflavones, notably genistein, which have a strong antioxidant capacity, are considered to regulate various signaling pathways, alleviate oxidative stress, and improve gut microbiota imbalance as well as mitochondrial dysfunction. In this literature review, we summarize the latest research on genistein, providing evidence of its development and application as a potential drug for preventing and treating five selected diseases (Parkinson's disease, Alzheimer's disease, diabetes mellitus, cardiovascular disease, and cancers). The literature was searched using keywords that include tripartite combinations of genistein and oxidative stress, along with each of the five selected diseases, from PubMed, Science Direct, and Google Scholar between 2014 and 2024. According to current in vitro, in vivo, and clinical trials, we comprehensively discuss the therapeutic dose used to target various disease entities to achieve optimal efficacy and meet safety requirements. Moreover, considering the poor water solubility and limited bioavailability of genistein, strategies for improving its therapeutic efficacy, such as combining it with exercise, existing medications, and advanced technologies, as well as applying nanotechnology, were assessed. Therefore, this review aims to provide robust evidence for the development and application of genistein as a potential therapeutic agent or functional food for preventing and treating these diseases.

Keywords:  anti-inflammatory; antioxidant; genistein; oxidative stress; signaling pathway

DOI:  https://doi.org/10.3390/antiox14080904
Antioxidants (Basel). 2025 Jul 23. pii: 902. [Epub ahead of print]14(8):

Mitochondrial Dysfunction and Oxidative Stress: Emerging Insights in Muscle and Cardiovascular Disease Mechanisms.

Marianne Riou, Bernard Geny.

Beyond their role as the "energy powerhouse" of the cell, mitochondria have emerged as essential actors in molecular signaling and determination of cellular fate, particularly through the production of reactive oxygen species (ROS) [...].

DOI: https://doi.org/10.3390/antiox14080902
Sci Rep. 2025 Aug 26. 15(1): 31326

Sex steroid hormones drive dimorphic responses in GDF15-deficient mouse models of cardiometabolic diseases.

Morgane Davezac, Mélissa Buscato, Rana Zahreddine, Faustine Darnaud, Pauline Auriol, Marine Adlanmerini, Pierre Gourdy, Jean-François Arnal, Françoise Lenfant, Coralie Fontaine.

  Growth Differentiation Factor 15 (GDF15) is recognized as a biomarker of cardiovascular disease, but its role in atherosclerosis remains unclear. Here, we investigated the role of GDF15 in atherosclerosis by crossing GDF15-deficient mice with LDLr-/- mice. Male GDF15-/- LDLr-/- mice fed a Western diet developed less atherosclerotic lesions than littermate controls despite exhibiting a pro-obesogenic phenotype, whereas GDF15 deficiency did not affect metabolism or lesion development in females. Plasma GDF15 levels were higher in male LDLr-/- mice than in females but were comparable to those measured in ovariectomized LDLr-/- females. Importantly, ovariectomy in females induced metabolic and vascular phenotypes similar to those of GDF15-/- LDLr-/- males, while gonadectomy in males had no effect, emphasizing the role of female steroid hormones in GDF15-related sexual dimorphism. These findings highlight the sex-specific effects of GDF15 on metabolism and atherosclerosis, underscoring the importance of sex and hormonal status in cardiometabolic disease management.

Keywords:  Atherosclerosis; GDF15; Metabolism; Mouse models; Sex differences; Steroid hormones

DOI:  https://doi.org/10.1038/s41598-025-13662-4
Antioxidants (Basel). 2025 Aug 06. pii: 968. [Epub ahead of print]14(8):

Camellia japonica Flower Extract and the Active Constituent Hyperoside Repair DNA Damage Through FUNDC1-Mediated Mitophagy Pathway for Skin Anti-Aging.

Hongqi Gao, Jiahui Shi, Guangtao Li, Zhifang Lai, Yan Liu, Chanling Yuan, Wenjie Mei.

  Skin aging is closely related to mitochondrial dysfunction and cell cycle abnormalities, and developing intervention strategies targeting mitochondrial quality control is an important direction for anti-aging research. In this study, we investigated the anti-aging mechanism of Camellia japonica flower (CJF) extract and its active ingredient hyperoside based on a doxorubicin (DOX)-induced endogenous senescence model in human skin fibroblasts (HSFs). LC-MS proteomics analysis revealed that CJF extract and hyperoside specifically activated the FUNDC1-mediated mitochondrial autophagy pathway, significantly ameliorated the DOX-induced decrease in mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS), and alleviated the cellular S-phase blockade and reversed the high expression of senescence-associated β-galactosidase (SA-β-gal). Further studies showed that the two cleared damaged mitochondria by enhancing mitochondrial autophagy and restoring cellular energy metabolism homeostasis while promoting type III collagen and elastin synthesis and repairing the expression of Claudin 1 related to skin barrier function. For the first time, the present study reveals the molecular mechanism of CJF extract in delaying skin aging by regulating the FUNDC1-dependent mitochondrial autophagy pathway, which provides a theoretical basis and a candidate strategy for developing novel anti-aging agents targeting mitochondrial quality control.

Keywords:  Camellia japonica flower extract; DNA damage; FUNDC1-mediated mitophagy pathway; hyperoside; skin anti-aging

DOI:  https://doi.org/10.3390/antiox14080968
J Adv Res. 2025 Aug 21. pii: S2090-1232(25)00644-7. [Epub ahead of print]

Mitochondrial DNA methylation: State-of-the-art in molecular mechanisms and disease implications.

Meng-Ting Yin, Liang Guo.

   BACKGROUND: Mitochondrial DNA (mtDNA), a circular genome essential for cellular energy production, is increasingly recognized to exhibit aberrant methylation under pathological conditions. Dysregulated methylation in regulatory regions can impair mtDNA replication, transcription, and metabolic homeostasis, thereby promoting disease progression, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, as well as aging. Despite challenges posed by nuclear pseudogene interference, advanced detection technologies have significantly improved the resolution of mtDNA methylation analysis.
AIM OF REVIEW: This review focuses on three key mtDNA methylation patterns, 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and N6-methyladenine (6mA), summarizing the evidence for their existence as well as their molecular mechanisms in diseases and offering insights into recent advances in mtDNA detection techniques. Key Scientific Concepts of Review: Under pathological conditions, the dysregulation of mtDNA methylation highlights its emerging promise as both a biomarker and therapeutic target. Therefore, this epigenetic aberration provides a foundational framework for elucidating the molecular mechanisms underlying mitochondrial dysfunction across diverse diseases and advancing precision medicine strategies.

Keywords:  5-hydroxymethylcytosine; 5-methylcytosine; MtDNA methylation; N6-methyladenine

DOI:  https://doi.org/10.1016/j.jare.2025.08.029
Aging (Albany NY). 2025 Aug 25. 17

Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.

Anna Panfilova, Tatiana Zubareva, Ekaterina Mironova, Gianluigi Mazzoccoli, Maria Greta Pia Marasco, Sofya Balazovskaia, Peter Yablonsky, Igor Kvetnoy.

  Research in the field of mitochondrial biomarkers plays an important role in understanding the processes of cellular aging. Mitochondria are not only the energy centers of the cell, but also key regulators of signaling within the cell. They significantly affect the life and function of the cell. The aging process of cells is associated with various factors, including DNA damage, disruption of the cell cycle, changes in mitochondria, and problems with signal transmission. Mitochondrial dysfunction is a major contributor to cellular and organismal aging. As we age, there is an accumulation of dysfunctional mitochondria, leading to decreased efficiency of oxidative phosphorylation and increased production of reactive oxygen species. This review focuses on the main mitochondrial markers involved in the mechanisms of cell aging: DRP1, Prohibitin, Parkin, PINK1, MFF, VDAC, TOM. These signaling molecules are involved in mitochondrial fission and the mechanisms of mitochondria-dependent apoptosis, in the regulation of mitochondrial respiratory activity, ensuring the stability of the organization and copying of mitochondrial DNA, protecting cells from oxidative stress, in the process of autophagy of damaged mitochondria, in protective mechanisms during stress-induced mitochondrial dysfunction. Analysis of mitochondrial markers can provide valuable information about the state of cells and their functional significance at various stages of aging, which could promote our understanding of cellular aging mechanisms and developing corrective methods. These insights highlight mitochondrial proteins as potential therapeutic targets to combat age-related diseases.

Keywords:  age-associated diseases; biomarkers; cellular senescence; mitochondria; mitochondrial proteins

DOI:  https://doi.org/10.18632/aging.206305
Research (Wash D C). 2025 ;8 0832

Emerging Roles of GDF15 in Metabolic and Cardiovascular Diseases.

Tian Tian, Monan Liu, Peter J Little, Hans Strijdom, Jianping Weng, Suowen Xu.

Growth differentiation factor 15 (GDF15), a TGF-β superfamily member and stress-responsive cytokine, plays a critical role in metabolism and regulation of inflammation. This review summarizes the expression, distribution, structure, processing, and secretion of GDF15. We also discuss multilayered regulatory networks governing GDF15 expression, including ATF4/CHOP, AMPK, EGR1, EZH2, PPARγ, NRF2, ERRγ, and p53, as well as posttranscriptional regulator CNOT6L. The GFRAL receptor is central to its function, mediating the anorexigenic and metabolic effects of GDF15. This review synthesizes evidence linking GDF15 to obesity, diabetes, cardiovascular diseases, metabolic liver disorders, cachexia, sarcopenia, and aging while exploring its interactions with key metabolic factors including FGF21, GLP-1, leptin, and glucocorticoids. Lifestyle interventions such as ketogenic, high-fat diets, and exercise modulate GDF15 levels, underscoring its role in pan-metabolic health. Pharmacologically, various agents-including anti-hyperglycemic agents and natural compounds-induce GDF15 expression, implicating their therapeutic potential in cardiometabolic diseases. We comprehensively evaluate current advances in GDF15-targeted drug development, including monoclonal antibodies, fusion proteins, and small-molecule drugs, to provide a scientific foundation for innovative therapies. Finally, we outline unresolved issues in GDF15 biology and therapeutics, such as the exploration of peripheral receptors, contradictory findings in studies of cardiometabolic diseases, and the persistent challenges in developing GDF15-targeted therapeutics.

DOI: https://doi.org/10.34133/research.0832
Mol Med Rep. 2025 Nov;pii: 296. [Epub ahead of print]32(5):

MitoQ alleviates malathion‑induced hepatorenal toxicity via oxidative stress and inflammation modulation.

Saed A Althobaiti.

  Malathion, a commonly used organophosphate pesticide, induces severe hepatorenal toxicity, mitochondrial dysfunction and inflammatory responses primarily through oxidative stress and apoptosis. The present study investigated the protective effects of mitoquinol (MitoQ), a mitochondria‑targeted antioxidant, against malathion‑induced toxicity in male Wistar albino rats. A total of 50 rats were divided into the following five groups: i) Control; ii) malathion‑only; iii) malathion + MitoQ; iv) MitoQ‑only; and v) vehicle. Malathion exposure significantly elevated the levels of aspartate aminotransferase, alkaline phosphatase, creatinine, urea and uric acid and decreased total protein, albumin and globulin levels. At the mitochondrial level, malathion reduced antioxidant enzyme activity (superoxide dismutase, glutathione peroxidase and glutathione) and ATP production while increasing reactive oxygen species, leading to oxidative damage. Furthermore, malathion induced upregulation of pro‑apoptotic markers such as Bax, and downregulation of the anti‑apoptotic marker, Bcl‑2. In addition, malathion increased TNF‑α, NF‑κB, Toll‑like receptor (TLR) 2 and TLR4 expression, and malathion toxicity induced severe hepatorenal damage, including vascular congestion, inflammatory infiltration and tubular degeneration. MitoQ co‑administration revealed a trend towards mitigating altered hepatorenal markers, inflammatory markers and regulated apoptotic/antiapoptotic gene markers, with partial restoration in mitochondrial function and histopathological changes. In parallel, MitoQ normalized cellular changes induced by malathion in the liver and kidneys. In conclusion, malathion toxicity in the liver and kidneys is mediated by mitochondrial oxidative stress, apoptosis and inflammation. MitoQ exerts protective effects by restoring mitochondrial homeostasis, reducing inflammatory signaling and mitigating tissue damage. Future research should explore longer treatment durations and potential synergistic effects with other antioxidants to optimize protection against pesticide‑induced toxicity.

Keywords:  apoptosis; hepatorenal damage; inflammation; malathion; mitochondrial dysfunction; mitoquinol; oxidative stress

DOI:  https://doi.org/10.3892/mmr.2025.13661
Reprod Sci. 2025 Aug 27.

Liquiritigenin Restores Declined Oocyte Quality and Improves Embryo Development in Aged Mice.

Yelan Cai, Jiawei Ma, Haifeng Xu, Huamei Jian, Wenyi Gao, Man Wu, Bailin Liu, Ying Chen.

  Ovarian aging leads to a decline in oocyte quality and reduced reproductive potential, which is one of the main challenges faced by assisted reproductive technology (ART). Oxidative stress (OS) is a major contributor to this decline. In this study, we investigated the protective effects of natural flavonoid compound liquiritigenin (LQ) on oocyte maturation and embryo development in aged mice. The results showed that 20 μM LQ significantly improved the maturation rate of aged oocytes, restored spindle morphology, and enhanced fertilization and two-cell embryo development rates. Mechanism studies have found that LQ reduces the levels of reactive oxygen species (ROS) in oocytes and restores mitochondrial function, including distribution patterns and membrane potential. Additionally, LQ upregulated the protein expression of Sirtuin 1 (SIRT1) and nuclear factor E2-related factor 2 (NRF2) in the ovaries and oocytes of aging mice, as well as in the human ovarian granulosa tumor cell line (KGN). Although its mRNA level showed minimal change, it suggested that it might play a role through post-translational regulation. These results suggest that LQ protects aged oocytes from oxidative stress by activating the SIRT1/NRF2 signaling pathway, highlighting its potential as a natural antioxidant for alleviating ovarian aging and improving oocyte quality.

Keywords:  Aged oocyte; Liquiritigenin; NRF2; Oxidative stress; SIRT1

DOI:  https://doi.org/10.1007/s43032-025-01959-8
Genes (Basel). 2025 Aug 13. pii: 957. [Epub ahead of print]16(8):

Dual Nature of Mitochondrial Integrated Stress Response: Molecular Switches from Protection to Pathology.

Jisu Jeong, Junghyun Kim, Man S Kim.

   BACKGROUND: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape.
METHODS: We reviewed recent literature (2020-2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches.
RESULTS: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The "dark microglia" phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement.
CONCLUSIONS: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms.

Keywords:  cellular adaptation; eIF2α phosphorylation; integrated stress response; mitochondrial dysfunction; neurodegeneration; precision medicine

DOI:  https://doi.org/10.3390/genes16080957
Nat Commun. 2025 Aug 25. 16(1): 7671

Ankyrin-B modulates mitochondrial fission in skeletal muscle and is required for optimal endurance exercise capacity.

Kayleigh M Voos, Joyce Tzeng, Priya Patel, Sophie Rubinsky, Ha E Choi, Trevor Pharr, Sebastian Sookram, Joseph A Baur, Erik J Soderblom, Damaris N Lorenzo.

Mitochondrial dynamics enable cellular adaptation to fluctuations in energy demand, such as those imposed on skeletal muscle by exercise, metabolic disorders, or aging. Here, we report a novel pathway that modulates mitochondria dynamics in skeletal muscle involving the scaffolding protein ankyrin-B. Rare variants in ankyrin-B, encoded by ANK2, increase risk for cardio-metabolic syndrome in humans and mice. We show that mice selectively lacking skeletal muscle ankyrin-B have reduced endurance exercise capacity without alterations in muscle strength or systemic glucose regulation. Muscle fibers in these mice have increased oxidative stress, reduced fatty acid oxidation, and enlarged and hyperconnected mitochondria. We found that ankyrin-B interacts with and is required for efficient mitochondria recruitment of fission modulators and sarcoplasmic reticulum-mitochondria coupling. Thus, we conclude that ankyrin-B enables substrate adaptability and bioenergetic homeostasis under energetic stress, and exercise capacity by promoting efficient mitochondrial fission in skeletal muscle.

DOI: https://doi.org/10.1038/s41467-025-62977-3
Transl Psychiatry. 2025 Aug 25. 15(1): 316

Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer's disease.

Vanessa Budny, Iván Ruminot, Maha Wybitul, Valerie Treyer, L Felipe Barros, Christian Tackenberg.

The human brain has high energy demands and tightly regulated mechanisms ensure its activity-dependent energy supply. Glucose hypometabolism is associated with brain aging and has also been linked to neurodegenerative diseases such as Alzheimer's disease (AD). The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for AD while APOE2 reduces the risk and APOE3 has been referred to as risk neutral allele. APOE is a major lipid carrier in the brain and is not only involved in the build-up of the two AD hallmark pathologies, β-amyloid (Aβ) plaques and neurofibrillary tangles, but also in several other (patho-)physiological processes including immune response, neuronal growth, synaptic plasticity and energy metabolism. Although there has been recent progress in understanding APOE biology, the exact mechanisms of how APOE (especially APOE4) affects brain energy metabolism are still largely unclear. This review highlights the recent evidence of how APOE isoforms differentially affect the bioenergetic homeostasis of the brain, thereby affecting AD etiology and pathophysiology, and identifies critical questions and emerging topics that require further investigation.

DOI: https://doi.org/10.1038/s41398-025-03550-w
Nutrients. 2025 Aug 09. pii: 2595. [Epub ahead of print]17(16):

EGCG and Taurine Synergistically Ameliorate Lipid Metabolism Disorder by Modulating Gut Microbiota and PPARα/FAS Signaling Pathway.

Yang Xiao, Mingyue Yang, Meihong Cai, Haihui Zhang, Kai Hu, Yuqing Duan.

   BACKGROUND/OBJECTIVES: The synergistic effects of epigallocatechin gallate (EGCG) and taurine in modulating lipid metabolism abnormalities in rats were investigated, and along with their potential mechanisms.
METHODS/RESULT: Compared to intervention with EGCG/taurine alone, EGCG combined with taurine (1:3) not only reduced triglyceride (TG) generation in HepG2 cells (46.2%, 75.2%, respectively), but also significantly decreased the total cholesterol (TC) (33.3%, 41.8%), low-density lipoprotein cholesterol (LDL-C) (32.3%, 29.2%) in rats, while the high-density lipoprotein cholesterol (HDL-C) increased by 12.7% and 33.5%. In addition, the combination of EGCG and taurine not only inhibited lipogenic enzyme activity, but also enhanced the levels of lipid catabolic enzymes and antioxidant enzymes, and alleviated hepatic injury. Furthermore, it significantly modulated gut microbiota composition by altering the abundances of Bacteroidetes, Firmicutes, and Proteobacteria, improving intestinal flora balance. Metabolomic profiling showed that reducing N-linoleoyl proline, cortisol, and 3-isocholanolic acid, and increasing phospholipid metabolites are the main ways methods for normalizing lipid metabolism in rats. The combination also elevated short-chain fatty acid (SCFA) synthesis, preserving intestinal barrier integrity; it also promoted lipid catabolism and energy expenditure via activating Peroxisome proliferator- activated receptor alpha (PPARα) and suppressing hepatic fatty acid synthase (FAS)- mediated lipogenesis.
CONCLUSION: These findings indicated that EGCG and taurine can synergistically regulate lipid metabolism abnormalities, which may offer a strategy for regulating lipid metabolism anomalies.

Keywords:  EGCG; PPARα/FAS; gut microbiota; lipid metabolism abnormalities; metabolomics; taurine

DOI:  https://doi.org/10.3390/nu17162595
Biogerontology. 2025 Aug 27. 26(5): 172

Zuogui and Yougui pills extend lifespan and improve ageing biomarkers via kaempferol-mediated mitophagy in Caenorhabditis elegans.

Wendi Chen, Shuang Liu, Guoqiang Xu, Xin Liu, Yuxuan Shi, Guolong Wang, Yunna Ning, Zhiming Lu, Yongzhi Cao, Yueran Zhao.

  Zuogui pill (ZGP) and Yougui pill (YGP) are classical kidney-tonifying formulas in Traditional Chinese Medicine, widely used clinically but with their potential to delay ageing and improve ageing biomarkers remaining unclear. This study combined network pharmacology and Caenorhabditis elegans models to investigate the anti-ageing effects and mechanisms of ZGP and YGP. Both formulas significantly extended lifespan (ZGP dose-dependently at 5-20 mg/mL; YGP at 20 mg/mL) and improved ageing biomarkers, as evidenced by enhanced motility, reduced lipofuscin accumulation and endogenous ROS levels, and increased resistance to heat and oxidative stress. Network analysis identified quercetin and kaempferol as the top-ranked shared active components. Subsequent experimental validation demonstrated that kaempferol (0.05-0.2 mM) replicated these pro-longevity effects and was shown to act by inducing mitophagy: it triggered an initial decrease followed by a long-term increase in mitochondrial content, concomitant with upregulated expression of mitophagy genes. Crucially, the lifespan-extending effects of kaempferol, ZGP, and YGP were completely abolished in bec-1 and pink-1 null mutants. This study establishes that ZGP and YGP delay ageing and improve ageing biomarkers in C. elegans by activating BEC-1/PINK-1-dependent mitophagy. Kaempferol was identified as a major active component mediating this effect, highlighting a key mechanism for the pro-longevity properties of these traditional formulas.

Keywords:   C. elegans ; Kaempferol; Lifespan; Mitophagy; Yougui pill; Zuogui pill

DOI:  https://doi.org/10.1007/s10522-025-10317-9
Fluids Barriers CNS. 2025 Aug 25. 22(1): 88

Endothelial mitochondria in the blood-brain barrier.

Yunwei Shao, Lingling Mai, Ruogu Qiao, Yi Liang, Yuying Jiao, Judith Homburg, Zhenfu Jiang, Laiyu Song.

  The blood-brain barrier (BBB) is a highly selective interface between the peripheral circulation and the central nervous system (CNS), crucial for maintaining brain homeostasis. Disruptions to the BBB, such as increased permeability or structural damage, can lead to neurological damage. Mitochondria, the primary energy producers within endothelial cells, play a key role in the function of the BBB by maintaining its integrity and low permeability. This review first outlines the structural components of the BBB, then examines the role of mitochondria in endothelial cells under physiological conditions. We further focus on alterations in mitochondrial function during pathological states, discussing their impact on BBB stability. Briefly, this review explores the involvement of mitochondria in BBB endothelial cells in both physiological processes and the pathological progression of neurological diseases, while proposing potential therapeutic directions for treating CNS disorders.

Keywords:  Blood-brain barrier; Endothelial cells; Mitochondria; Nervous system

DOI:  https://doi.org/10.1186/s12987-025-00699-w
Biomolecules. 2025 Aug 13. pii: 1159. [Epub ahead of print]15(8):

Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk.

Sakthijothi Muthu, Zinnia Tran, Ramasamy Saminathan, Pratikshya Shrestha, Sundararajan Venkatesh.

  Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1CKO-HET) and a whole-body heterozygous knockout (Lonp1GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling.

Keywords:  LONP1; cardiac dysfunction; heart; mitochondria; mitochondrial dysfunction; mitochondrial matrix; protein quality control

DOI:  https://doi.org/10.3390/biom15081159
Pharmaceuticals (Basel). 2025 Aug 19. pii: 1222. [Epub ahead of print]18(8):

Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging.

Amelia Tero-Vescan, Hans Degens, Antonios Matsakas, Ruxandra Ștefănescu, Bianca Eugenia Ősz, Mark Slevin.

  Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines-particularly IL-6, irisin, leptin, and adiponectin-in orchestrating muscle-adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health.

Keywords:  IL-6; adipokines; adiponectin; irisin; leptin; metabolic flexibility; mitochondrial biogenesis; myokines; skeletal muscle–adipose tissue crosstalk

DOI:  https://doi.org/10.3390/ph18081222
J Clin Med. 2025 Aug 18. pii: 5834. [Epub ahead of print]14(16):

The Final Phases of Ovarian Aging: A Tale of Diverging Functional Trajectories.

Stefania Bochynska, Miguel Ángel García-Pérez, Juan J Tarín, Anna Szeliga, Blazej Meczekalski, Antonio Cano.

  Ovarian aging is characterized by a gradual decline in both reproductive and endocrine functions, ultimately culminating in the cessation of ovarian activity around the age of 50, when most women experience natural menopause. The decline begins early, as follicular attrition is initiated in utero and continues throughout childhood and reproductive life. Most follicles undergo atresia without progressing through substantial stages of growth. With increasing age, a pronounced reduction occurs in the population of resting follicles within the ovarian reserve, accompanied by a decline in the size of growing follicular cohorts. Around the age of 38, the rate of follicular depletion accelerates, sometimes resulting in diminished ovarian reserve (DOR). The subsequent menopausal transition involves complex, irregular hormonal dynamics, manifesting as increasingly erratic menstrual patterns, primarily driven by fluctuations in circulating estrogens and a rising incidence of anovulatory cycles. In parallel with the progressive depletion of the follicular pool, the serum concentrations of anti-Müllerian hormone (AMH) decline gradually, while reductions in inhibin B levels become more apparent during the late reproductive years. The concomitant decline in both inhibin B and estrogen levels leads to a compensatory rise in circulating follicle-stimulating hormone (FSH) concentrations. Together, these endocrine changes, alongside the eventual exhaustion of the follicular reserve, converge in the onset of menopause, which is defined by the absence of menstruation for twelve consecutive months. The mechanisms contributing to ovarian aging are complex and multifactorial, involving both the oocyte and the somatic cells within the follicular microenvironment. Oxidative stress is thought to play a central role in the age-related decline in oocyte quality, primarily through its harmful effects on mitochondrial DNA integrity and broader aspects of cellular function. Although granulosa cells appear to be relatively more resilient, they are not exempt from age-associated damage, which may impair their hormonal activity and, given their close functional relationship with the oocyte, negatively influence oocyte competence. In addition, histological changes in the ovarian stroma, such as fibrosis and heightened inflammatory responses, are believed to further contribute to the progressive deterioration of ovarian function. A deeper understanding of the biological processes driving ovarian aging has facilitated the development of experimental interventions aimed at extending ovarian functionality. Among these are the autologous transfer of mitochondria and stem cell-based therapies, including the use of exosome-producing cells. Additional approaches involve targeting longevity pathways, such as those modulated by caloric restriction, or employing pharmacological agents with geroprotective properties. While these strategies are supported by compelling experimental data, robust clinical evidence in humans remains limited.

Keywords:  aging; diminished ovarian reserve; fertility; hormones; menopausal transition; ovary

DOI:  https://doi.org/10.3390/jcm14165834
Trends Cell Biol. 2025 Aug 26. pii: S0962-8924(25)00175-8. [Epub ahead of print]

Is mitochondrial function at the heart of ribosome-related diseases?

Qiuxia Zhao, Elif Sarinay Cenik.

  Defects in ribosomal machinery cause ribosomopathies such as Diamond Blackfan anemia, classically linked to impaired protein synthesis. However, emerging evidence places mitochondrial dysfunction as a critical downstream consequence of ribosomal insufficiency. Thus, is impaired energy metabolism, rather than translation alone, a key driver of ribosomopathies such as Diamond Blackfan anemia? This insight could reframe our understanding of disease mechanisms and could identify metabolic pathways as promising therapeutic targets.

Keywords:  mitochondrial function; mitochondriopathies; ribosome biogenesis; ribosomopathies

DOI:  https://doi.org/10.1016/j.tcb.2025.07.007
Antioxidants (Basel). 2025 Jul 27. pii: 919. [Epub ahead of print]14(8):

Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging.

Kiyotaka Yamada, Masami Ito, Haruka Nunomura, Takashi Nishigori, Atsushi Furuta, Mihoko Yoshida, Akemi Yamaki, Kanto Shozu, Ippei Yasuda, Sayaka Tsuda, Tomoko Shima, Akitoshi Nakashima.

  Organ functions generally decline with age, but the ovary is a prototypical organ that undergoes functional loss over time. Autophagy plays a crucial role in maintaining organ homeostasis, and age-related upregulation of the autophagy inhibitor protein, Rubicon, has been linked to cellular and tissue dysfunction. This review describes how granulosa cell autophagy supports follicular growth and oocyte selection and maturation by regulating cellular energy metabolism and protein quality control. We then introduce the role of selective autophagy, including mitophagy or lipophagy, in steroidogenesis and cellular remodeling during luteinization. In aged ovaries, Rubicon accumulation suppresses autophagic flux, leading to diminished oxidative-stress resilience and enhanced DNA damage. Moreover, impaired autophagy drives the accumulation of ATP citrate lyase, which correlates with poor oocyte quality and reduced ovarian reserve. Following fertilization, oocytes further upregulate autophagy to provide the energy required for blastocyst transition. Conversely, in infertility-related disorders, such as premature ovarian insufficiency, endometriosis, and polycystic ovary syndrome, either deficient or excessive autophagy contributes to disease pathogenesis. Both autophagy inhibitors (e.g., Rubicon) and activators (e.g., Beclin1) could be emerging as promising biomarkers for assessing ovarian autophagy status. Therapeutically, Rubicon inhibition by trehalose in aged ovaries and autophagy suppression by agents such as hydroxychloroquine in polycystic ovary syndrome and endometriosis hold potential. Establishing robust methods to evaluate ovarian autophagy will be essential for translating these insights into targeted treatments.

Keywords:  autophagy; granulosa cells; ovarian aging; oxidative stress; rubicon

DOI:  https://doi.org/10.3390/antiox14080919
Int J Mol Sci. 2025 Aug 11. pii: 7740. [Epub ahead of print]26(16):

Mild Mitochondrial Uncoupling for True Ectopic Lipid Disposal.

Hui-Young Lee.

  Ectopic lipid accumulation is a core contributor to insulin resistance and metabolic diseases, including type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Conventional therapies have primarily focused on redistributing lipid burden across tissues or modulating specific pathways. However, this often causes compensatory responses that merely shift the burden rather than resolve the underlying lipid excess. In this review, we introduce the concept of the ballooning effect, wherein single-target interventions inadvertently exacerbate lipid accumulation in non-target tissues. We then explore fundamental strategies for true lipid disposal, which aim either to prevent lipid influx or to promote complete lipid oxidation. Among these, mild mitochondrial uncoupling emerges as a promising solution. By dissipating substrate energy as heat, mitochondrial uncoupling reduces ectopic lipid burden without relying on redistribution. Recent advances have yielded safer chemical uncouplers and novel endogenous protein-based mechanisms that enable controlled uncoupling with minimal toxicity. Together, these provide a new framework for next-generation metabolic therapies that move beyond lipid redistribution and aim for a true lipid disposal, potentially offering a safe and effective strategy.

Keywords:  ballooning effects; ectopic lipids; metabolic diseases; mitochondrial uncoupling

DOI:  https://doi.org/10.3390/ijms26167740
Int Immunopharmacol. 2025 Aug 20. pii: S1567-5769(25)01366-9. [Epub ahead of print]164 115375

Epigallocatechin gallate-mediated inhibition of mitochondrial DNA sensing regulated by TBK1/cGAS/STING and NLRP3 alleviates cardiovascular toxicity in atherosclerosis.

Feifei Li, Yuanshen Zhou, Baoning Liu, Zhimin Du, Wenxiang Huang.

  Epigallocatechin gallate (EGCG) exerts cardio-protective effects. This study aimed to investigate the effects of EGCG on atherosclerosis (AS) and the potential mechanisms. High-fat diet was used to establish mice AS mouse model. Histological analysis was performed using HE and Masson staining. Gene expression was detected using RT-qPCR, Western blot, and immunofluorescence. Cytokine release was detected using ELISA. ox-LDL was used to establish in vitro AS model. Cellular functions were determined using TUNEL and flow cytometry assays. Mitochondrial functions were determined using Seahorse assays, mitoSOX staining, flow cytometry and TMRM staining. We found that EGCG effectively improved the cardiac haemodynamics and alleviated the fibrosis of myocardial cells. Mechanistically, EGCG maintained mitochondrial homeostasis and inhibited mitochondrial oxidative stress in vascular endothelial cells. Moreover, EGCG inhibited mtDNA release, TBK1-cGAS-STING-mediated cytotoxicity and subsequent apoptosis of vascular endothelial cells, suppressing M1 macrophage polarization. M1 macrophages further enhanced the apoptosis of vascular endothelial cells. Strikingly, RU.521 plus EGCG exerted more potent effects on inhibiting cGAS-STING signaling, M1 macrophage polarization, and apoptosis of vascular endothelial cells. Taken together, EGCG protects against AS through alleviating TBK1/cGAS/STING/NLRP3 signaling-mediated dysfunction of vascular endothelial cells in AS.

Keywords:  Epigallocatechin gallate; Mitochondrial DNA; Pyroptosis; atherosclerosis

DOI:  https://doi.org/10.1016/j.intimp.2025.115375
Cell Death Dis. 2025 Aug 27. 16(1): 652

Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.

Yanling Chen, Xun Liu, Yixuan Liu, Yujia Li, Dingxiang Li, Zhigang Mei, Yihui Deng.

Diabetes mellitus (DM), a metabolic disease of globally health concern, is pathologically attributed to mitochondrial dysfunction, an essential component in disease progression. Mitochondrial quality control (MQC) acts as a critical defense mechanism for metabolic homeostasis, yet its implications in DM and its complications remain incompletely understood. This study thoroughly summarizes emerging evidence that delineates the molecular processes of MQC, with an emphasis on effector protein post-translational regulation, upstream signaling hubs, and interactions with other metabolic processes including ferroptosis and lipid metabolism. We highlight newly discovered processes involving mitochondrial-derived vesicles, licensed mitophagy, and mitocytosis that broaden the regulatory landscape of MQC, going beyond the traditionally recognized process including biogenesis, dynamics and mitophagy. MQC imbalance exacerbates insulin resistance, while impaired insulin signaling reciprocally compromises mitochondrial function, creating a vicious cycle of metabolic deterioration. Despite tissue-specific pathophysiology, diabetic complications exhibit identical MQC impairment including suppressed biogenesis, fission-fusion imbalance, and deficient mitophagy. Emerging therapies including clinical hypoglycemic agents and bioactive phytochemicals demonstrate therapeutic potential by restoring MQC. However, current strategies remain anchored to classical pathways, neglecting novel MQC mechanisms such as mitocytosis. Addressing this gap demands integration of cutting-edge MQC insights into drug discovery, particularly for compounds modulating upstream regulators. Future studies must prioritize mechanistic dissection of MQC novel targets and their translational relevance in halting metabolic collapse of diabetes progression. Since mitochondrial function is a cornerstone of metabolic restoration, synergizing precision MQC modulation with multi-target interventions, holds transformative potential for refine diabetic complications therapeutics.

DOI: https://doi.org/10.1038/s41419-025-07936-y
Int J Mol Sci. 2025 Aug 15. pii: 7887. [Epub ahead of print]26(16):

Systems and Molecular Biology of Longevity and Preventive Medicine: Brain-Energy-Microbiome-Exposome Synergies in Blue Zones and the Cilento Case.

Silvana Mirella Aliberti, Mario Capunzo, Richard H W Funk.

  Longevity and healthy aging result from the complex interaction of genetic, epigenetic, microbial, behavioral, and environmental factors. The central nervous system-particularly the cerebral cortex-and the autonomic nervous system (ANS) play key roles in integrating external and internal signals, shaping energy metabolism, immune tone, and emotional regulation. This narrative review examines how the brain-ANS axis interacts with epigenetic regulation, telomere dynamics, the gut microbiome, and the exposome to influence biological aging and resilience. Relevant literature published between 2010 and 2025 was selected through comprehensive database searches (PubMed, Scopus, Google Scholar), with a focus on studies addressing the multisystemic determinants of aging. Emphasis is placed on lifestyle-related exposures, such as diet, physical activity, psychosocial support, and environmental quality, that modulate systemic physiology through neurovisceral pathways. Drawing on empirical findings from classical Blue Zones and recent observational research in the Cilento region of southern Italy, this review highlights how context-specific factors-such as clean air, mineral-rich water, Mediterranean dietary patterns, and strong social cohesion-may foster bioelectric, metabolic, and neuroimmune homeostasis. By integrating data from neuroscience, systems biology, and environmental epidemiology, the review proposes a comprehensive model for understanding healthy longevity and supports the development of personalized, context-sensitive strategies in geroscience and preventive medicine.

Keywords:  Blue Zones; Cilento; autonomic nervous system; energy metabolism; epigenetics; exposome; gut–brain axis; healthspan; longevity; telomeres

DOI:  https://doi.org/10.3390/ijms26167887
Adv Sci (Weinh). 2025 Aug 21. e10242

Modulation of Aging Diseases via RAGE Targets: A Dietary Intervention Review.

Qian Wu, Jia Yan, Yuyan Zhang, Xiaozhi Ming, Siqi Chen, Zhichao Zou, Nianjie Feng, Jianbo Xiao.

  With the acceleration of global population aging, effective strategies for the prevention and management of aging-related diseases have become increasingly urgent. The receptor for advanced glycation end products (RAGE), a pattern recognition receptor of the immunoglobulin superfamily, plays a central regulatory role in the pathogenesis of chronic conditions such as diabetes and Alzheimer's disease. By binding to a wide range of ligands (e.g., advanced glycation end products, amyloid beta), RAGE activates key inflammatory and stress-related signaling pathways, including NF-κB and MAPK, positioning it as a critical therapeutic target. This review systematically examines RAGE-ligand interactions and their downstream signaling cascades, and proposes targeted intervention strategies. Special emphasis is placed on the regulatory potential of dietary bioactive compounds, such as polyphenols, polysaccharides, and terpenoids, highlighting the distinct advantages of functional foods in anti-aging applications. In line with the World Health Organization's concept of "preventive aging," dietary-based approaches offer a long-term, safe, and integrative means of providing both nutritional support and disease prevention. This review provides a theoretical foundation for the development of RAGE-targeted dietary interventions and supports a paradigm shift from medical treatment to nutritional prevention in anti-aging strategies.

Keywords:  RAGE; aging diseases; dietary; interaction; modulation

DOI:  https://doi.org/10.1002/advs.202510242
Cells. 2025 Aug 15. pii: 1260. [Epub ahead of print]14(16):

Mitochondrial Reactive Oxygen Species Production in Vascular Dementia Following Experimental Diabetes.

Ed Wilson Santos, Subika Khatoon, Yun-Min Zheng, Yong-Xiao Wang.

  Type 1 diabetes (T1D) is a serious disease which affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). In this study, we first characterized cognitive and memory impairments, then evaluated their underlying molecular mechanisms, and finally determined sex-dependent effects in male and female mice with streptozotocin (STZ)-induced T1D. Our findings indicated that significant cognitive impairment, memory loss, and vascular dementia occurred in male and female T1D mice. Cerebral artery (CA) blood flow was greatly reduced in the various brain regions tested. ROS generation in isolated cells, mitochondria, and mitochondrial complex III from CA smooth muscle cells (CASMCs) were all increased in T1D. DNA damage and Tau phosphorylation in CASMCs were largely increased. Linear regression analysis revealed that T1D-induced increased blood glucose was highly correlated with increased ROS production and increased VCID. Taken together, we conclude that T1D causes increased mitochondrial complex III ROS production, DNA damage, and Chk2 phosphorylation in CASMC, thereby leading to vascular dementia in both male and female mice; our results further demonstrate that mitochondrial complex III ROS-mediated DNA damage is more significant in male than female mice, which contributes to more serious vascular dementia in the former than the latter.

Keywords:  cerebral artery smooth muscle cell; cognitive impairment; dementia; diabetes; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/cells14161260