bims-mistre 2025-05-04 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–05–04
thirty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

Multiple pathways through which the gut microbiota regulates neuronal mitochondria constitute another possible direction for depression.
Systematic review of mitochondrial dysfunction and oxidative stress in aging: A focus on neuromuscular junctions.
Mitochondrial Dysfunction in Endothelial Cells: A Key Driver of Organ Disorders and Aging.
Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
Mitochondria-targeted rosmarinic acid: Its role against oxidative damage.
Triterpenoid CDDO-EA Protects from Hyperglycemia, Hyperinsulinemia, and Obesity by Decreasing Energy Intake.
Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.
Polydatin reactivates mitochondrial bioenergetics and mitophagy while preventing premature senescence by modulating microRNA-155 and its direct targets in human fibroblasts with trisomy 21.
Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.
Alzheimer's disease and the immune system: A comprehensive overview with a focus on B cells, humoral immunity, and immunotherapy.
Activation of spinal PGC-1α regulates microglial polarization through a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome in neuropathic pain.
Ketoglutaric acid treatment enhances the antioxidant status of broccoli sprouts.
Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.
Cyanidin-3-O-Glucoside Mitigates Amyloid-Beta (1-42)-Induced Apoptosis in SH-SY5Y Cells by Regulating Ca2+ Homeostasis and Inhibiting Mitochondrial Dysfunction.
Mitochondria-targeting natural product rhein conjugated with dichloroacetate as the dual inhibitor of glycolysis and oxidative phosphorylation to off energize cancer cells and induce ROS storm.
Glutathione Decreases Parkinsonism-Induced Ferroptosis and Oxidative Stress Through the Inhibition of the TRPM2 Channel in Neuronal Cells.
The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions.
Role of Reactive Oxygen Species in Collagen-Induced Platelet Activation and the Protective Effects of Antioxidants.
Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
Coenzyme Q10 protects keratinocytes against oxidation-induced energy stress as revealed by spatiotemporal analysis of cell energetics.
Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
PICK1 overexpression ameliorates endotoxin-induced acute lung injury by regulating mitochondrial quality control via maintaining Nrf-2 stabilization through activating the PI3K/Akt/GSK-3β pathway and disrupting the E3 ubiquitin ligase adapter β-TrCP.
Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes.
The interaction between metals and catecholamines: oxidative stress, DNA damage, and implications for human health.
Advanced Glycation End Products and Skin Autoimmune Disorders: Pathogenic Insights into Vitiligo, Bullous Pemphigoid, and Type 1 Diabetes Mellitus.
Aging and Lifestyle Modifications for Preventing Aging-Related Diseases.
Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques.
Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.
Exercise Mimetics in Aging: Suggestions from a Systematic Review.
Exercise Alleviates Atherosclerosis Through the Modulation of the NLRP3 Inflammasome.
Molecular Mechanisms and Therapeutic Perspectives of Luteolin on Diabetes and Its Complications.

Front Microbiol. 2025 ;16 1578155

Multiple pathways through which the gut microbiota regulates neuronal mitochondria constitute another possible direction for depression.

Hongyi Zhao, Xiongfeng Qiu, Shuyu Wang, Yi Wang, Li Xie, Xiuwen Xia, Weihong Li.

  As a significant mental health disorder worldwide, the treatment of depression has long faced the challenges of a low treatment rate, significant drug side effects and a high relapse rate. Recent studies have revealed that the gut microbiota and neuronal mitochondrial dysfunction play central roles in the pathogenesis of depression: the gut microbiota influences the course of depression through multiple pathways, including immune regulation, HPA axis modulation and neurotransmitter metabolism. Mitochondrial function serves as a key hub that mediates mood disorders through mechanisms such as defective energy metabolism, impaired neuroplasticity and amplified neuroinflammation. Notably, a bidirectional regulatory network exists between the gut microbiota and mitochondria: the flora metabolite butyrate enhances mitochondrial biosynthesis through activation of the AMPK-PGC1α pathway, whereas reactive oxygen species produced by mitochondria counteract the flora composition by altering the intestinal epithelial microenvironment. In this study, we systematically revealed the potential pathways by which the gut microbiota improves neuronal mitochondrial function by regulating neurotransmitter synthesis, mitochondrial autophagy, and oxidative stress homeostasis and proposed the integration of probiotic supplementation, dietary fiber intervention, and fecal microbial transplantation to remodel the flora-mitochondrial axis, which provides a theoretical basis for the development of novel antidepressant therapies targeting gut-brain interactions.

Keywords:  depression; gut microbiota; immune; intestinal-brain axis; neuronal mitochondria

DOI:  https://doi.org/10.3389/fmicb.2025.1578155
Neural Regen Res. 2025 Apr 29.

Systematic review of mitochondrial dysfunction and oxidative stress in aging: A focus on neuromuscular junctions.

Senlin Chai, Ning Zhang, Can Cui, Zhengyuan Bao, Qianjin Wang, Wujian Lin, Ronald Man Yeung Wong, Sheung Wai Law, Rebecca Schönmehl, Christoph Brochhausen, Wing Hoi Cheung.

   ABSTRACT: Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases. The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia. However, the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood. A defined systematic search of the PubMed, Web of Science and Embase databases (last accessed on October 30, 2024) was conducted with search terms including 'mitochondria', 'aging' and 'NMJ'. Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging. Twentyseven studies were included in this systematic review. This systematic review provides a summary of morphological, functional and biological changes in neuromuscular junction, mitochondrial morphology, biosynthesis, respiratory chain function, and mitophagy during aging. We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging. Aging is characterized by significant reductions in mitochondrial fusion/fission cycles, biosynthesis, and mitochondrial quality control, which may lead to neuromuscular junction dysfunction, denervation and poor physical performance. Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities, ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function. Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways, including the mitochondrial respiratory chain, energy deficiency, oxidative stress, and inflammation. Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation, resulting in muscle atrophy and a decrease in strength during aging. Physical therapy, pharmacotherapy, and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function. Therefore, mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.

Keywords:  aging; mitochondrial dysfunction; neuromuscular junction; oxidative stress; sarcopenia; systematic review

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01338
Antioxidants (Basel). 2025 Mar 21. pii: 372. [Epub ahead of print]14(4):

Mitochondrial Dysfunction in Endothelial Cells: A Key Driver of Organ Disorders and Aging.

Elena Grossini, Sakthipriyan Venkatesan, Mohammad Mostafa Ola Pour.

  Mitochondria are of great importance in cell biology since they are major sites of adenosine triphosphate (ATP) production and are widely involved in different cellular pathways involved in the response to stress. During ATP production, reactive oxygen species (ROS) can be produced. While a small amount of ROS may be important for the regulation of physiological processes, at elevated levels they can turn into harmful agents leading to cellular damage. From a pathological perspective, it could be particularly interesting to focus on mitochondrial function in endothelial cells since they may be involved in the development of aging and in the onset of different diseases, including renal, cardio-metabolic, liver and neurodegenerative ones. However, to date, there are no surveys which address the above issues. To fill this gap, it may be valuable to collect recent findings about the role of mitochondria in the regulation of endothelial function, not only to increase knowledge about it but also for clinical applications. Here, we overview the most recent knowledge about the above issues in the view of characterizing the role of mitochondria in endothelial cells as an innovative potential target for the prevention of aging, as well as the treatment of the above pathological conditions.

Keywords:  ageing; endothelial cells; liver diseases; mitochondria; neurodegenerative disorders; reactive oxygen species; renal diseases

DOI:  https://doi.org/10.3390/antiox14040372
Neural Regen Res. 2025 Apr 29.

Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.

Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue.

   ABSTRACT: The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; calcium homeostasis; intervention strategy; mitochondria; mitochondrial dysfunction; mitochondrial membrane permeability transition pore; mitophagy; neurodegenerative diseases; oxidative stress; targeted therapy

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01507
Biomed Pharmacother. 2025 Apr 30. pii: S0753-3322(25)00308-7. [Epub ahead of print]187 118114

Mitochondria-targeted rosmarinic acid: Its role against oxidative damage.

Antonella Girgenti, Pasquale Picone, Miriam Buttacavoli, Laura Palumbo, Flores Naselli, Elena Lo Presti, Desirée Pecora, Chiara Cipollina, Francesca Annunziata, Andrea Pinto, Lucia Tamborini, Domenico Nuzzo.

  Mitochondria plays a key role in the physiological function of neurons, and alteration of this organelle results in severe and irreversible cell damage. Altered mitochondrial activity usually leads to cell degeneration that compromises the function of the neuronal network. Oxidative stress represents the main critical point of this mitochondrial alteration. Research focuses on finding specific treatments for the mitochondrion to target molecules capable of acting in that specific organelle. In this study, we synthesized and evaluated a series of mitochondria-targeted compounds derived from natural phenolic acids, including caffeic, syringic, gallic and rosmarinic acid, intending to enhance their antioxidant and neuroprotective properties. Among these, MITO-rosmarinic was a highly effective compound, demonstrating the ability to mitigate oxidative stress-induced damage in neuronal cells. Our findings underscore the potential of MITO-rosmarinic as a candidate for preventing mitochondrial dysfunction in neurodegenerative diseases.

Keywords:  MITO-derivatives; Mitochondria; Natural phenolic acids; Neurodegeneration; Triphenylphosphonium cation

DOI:  https://doi.org/10.1016/j.biopha.2025.118114
bioRxiv. 2025 Feb 15. pii: 2025.02.12.636924. [Epub ahead of print]

Triterpenoid CDDO-EA Protects from Hyperglycemia, Hyperinsulinemia, and Obesity by Decreasing Energy Intake.

Austin E Cantu, Cordelia Rasa, Shizue Mito, Denae Cantu, Juan Carlos Lopez-Alvarenga, Leslie Rivera-Lopez, Israel Rios, Ashley Abrego-Gonzalez, Sara M Reyna.

Obesity is a significant factor in the development of type 2 diabetes (T2D). Treatment of obesity is pivotal in the prevention and management of T2D, and the development of new pharmacological therapies are studied for improving insulin resistance and glucose intolerance. Oleanolic acid derived triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acids (CDDOs), are studied to elucidate the mechanisms by which they protect against obesity. However, there remain fundamental gaps in knowledge regarding the physiological and molecular mechanisms by which CDDOs protect against obesity. Our recently published studies showed that CDDO-ethyl amide (CDDO-EA) prevents skeletal muscle inflammation by inhibiting activation of nuclear factor kappa B (NF- κ B) signaling. Moreover, CDDO-EA induced translocation of the glucose transporter, GLUT4, in skeletal muscle cells. We hypothesized that CDDO-EA protects from obesity-induced hyperglycemia in mice fed a high fat diet (HFD). Our results show that CDDO-EA protects from HFD-induced obesity but has no effect on body weight in mice fed a low-fat diet (LFD). Our data show that CDDO-EA inhibition of weight gain is associated with reduced caloric intake and glucose and insulin levels in mice fed a HFD. This highlights the potential of CDDO-EA as a therapeutic agent for obesity treatment and the protection against the development of T2D.
IMPACT STATEMENT: The significance of our studies is that they define factors affected by CDDOs to maintain energy homeostasis and improve glucose metabolism to protect against obesity-induced insulin resistance. Our work examines metabolic factors affected by CDDO-EA by demonstrating that CDDO-EA protects from weight gain, glucose intolerance, and insulin resistance. Our research adds new knowledge on the anti-obesity and anti-diabetic properties of CDDO-EA by showing that incorporation of CDDO-EA in a high fat diet prevents obesity and an increase in glucose and insulin levels in an animal model of obesity and insulin resistance. Importantly, CDDO-EA incorporated in a low-fat diet does not affect body weight and caloric intake. Given that obesity is the major risk factor in the progression to T2D, our investigation on characterizing the metabolic effects of CDDO-EA on obesity advances and facilitates the use of CDDOs as candidates for the prevention and treatment of T2D.

DOI: https://doi.org/10.1101/2025.02.12.636924
Antioxid Redox Signal. 2025 Apr 26.

Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.

Miguel González-Hernández, Laura Gallardo-Andalucía, Pablo Hernansanz-Agustín.

  Background: Inflammation is one of the most important pathways in innate immunity and its relationship with redox biology is becoming increasingly clear in the last decades. However, the specific redox modes and pathways by which inflammation is produced are not yet well defined. Significance: In this review, we provide a general explanation of the reactive oxygen species (ROS) production and quenching modes occurring in mammalian mitochondria, as well as a summary of the most recent advances in mitochondrial redox biology and bioenergetics regarding sodium (Na+) homeostasis. In addition, we provide a collection of examples in which several inflammatory pathways have been associated with specific modes of either mitochondrial ROS production or quenching. Innovation: The role of Na+ in mitochondrial biology is being developed. Since its discovery as a second messenger, the research of its role in the immune system has emerged. Now, the role of Na+ in mitochondrial bioenergetics has recently been identified, which owns unprecedented applications. The potential implication of Na+ in inflammatory mechanisms grows as its role does not only cover ROS production and respiration but also the control through the management of mitochondrial membrane potential. Future directions: Na+ is becoming relevant for mitochondrial biology. Thus, processes regarding mitochondrial bioenergetics, redox state, or metabolism may probably need to include the study of Na+ in their road map. Some of these pathways are involved in inflammation and more are possibly to come. This review is expected to serve as a bridge between both fields. Antioxid. Redox Signal. 00, 000-000.

Keywords:  ROS; antioxidant system; bioenergetics; inflammation; mitochondria; sodium

DOI:  https://doi.org/10.1089/ars.2024.0737
Free Radic Biol Med. 2025 Apr 23. pii: S0891-5849(25)00242-4. [Epub ahead of print]

Polydatin reactivates mitochondrial bioenergetics and mitophagy while preventing premature senescence by modulating microRNA-155 and its direct targets in human fibroblasts with trisomy 21.

Daniela Valenti, Daniela Isabel Abbrescia, Flaviana Marzano, Giampietro Ravagnan, Apollonia Tullo, Rosa Anna Vacca.

  Mitochondrial dysfunction and redox dyshomeostasis are considered crucial factors causally linked to the pathogenesis of Down syndrome (DS), a human genetic anomaly currently lacking a cure, associated with neurodevelopmental deficits in children and early onset symptoms of aging in adults. Several natural plant-derived polyphenolic compounds, known for their neurostimulator, antioxidant and anti-inflammatory activities, have been proposed as dietary supplements to manage DS-linked phenotypic alterations. However, the poor bioavailability and rapid metabolism of these compounds have limited conclusive evidence regarding their clinical efficacy in individuals with DS. Polydatin (PLD), a natural polyphenolic glucoside precursor of resveratrol derived from Polygonum cuspidatum, is instead highly bioavailable and resistant to enzymatic oxidation. PLD supplementation has shown many therapeutic efficacies in several human diseases without side effects. In this study, we used fetal trisomy 21 human skin fibroblasts (DS-HSFs) to investigate, from a mechanistic point of view, whether PLD supplementation could prevent or counteract critical cellular alterations linked to both neurodevelopmental deficits and early aging in DS. Our findings demonstrate that PLD reactivates mitochondrial bioenergetics, reduces oxygen radical overproduction and prevents oxidative stress (OS)-induced cellular senescence and DNA damage in DS-HSF. Notably, we identified a novel mechanism of PLD action involving the chromosome-21-encoded microRNA-155 (miR-155) and its direct target genes casitas B-lineage lymphoma (CBL), BAG Cochaperone 5 (BAG5) and mitochondrial transcription factor A (TFAM). These proteins play pivotal roles in regulating mitochondrial bioenergetics, biogenesis and mitophagy. Given that the deregulation of miR-155/CBL axis is also implicated in acute leukemias, which frequently occur in children with DS, PLD emerges as a promising candidate for translational application. Its ability to enhance mitochondrial bioenergetics and address critical DS-associated phenotypic alterations highlights its therapeutic potential.

Keywords:  BAG Cochaperone 5; Down syndrome; Polydatin supplementation; aging; casitas B-lineage lymphoma; leukemia; miR-155; mitochondrial bioenergetics; mitophagy; oxidative stress; senescence

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.032
Antioxidants (Basel). 2025 Apr 08. pii: 446. [Epub ahead of print]14(4):

Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.

Beatrice Casorati, Isabella Zafferri, Sara Castiglioni, Jeanette A Maier.

  Mesenchymal stem cells (MSCs) are multipotent progenitors capable of self-renewal and differentiation into various cell lineages, making them essential for tissue repair and regenerative medicine. However, their regenerative potential is constrained by replicative senescence, an irreversible growth arrest that occurs after a finite number of cell divisions. In this study, we serially passaged human bone marrow-derived MSCs (bMSCs) and compared young, pre-senescent, and senescent cells. The onset of senescence was accompanied by progressive alterations in mitochondrial dynamics, leading to a decline in mitochondrial membrane potential, and increased reactive oxygen species (ROS) production, alongside a diminished cellular antioxidant capacity. These mitochondrial defects play a role in metabolic reprogramming in senescent bMSCs. Our findings underscore the intricate interplay between ROS, mitochondrial dysfunction, and replicative senescence, offering valuable insights to guide the development of therapeutic strategies for preserving MSC functionality in aging and MSC-based therapies.

Keywords:  ROS; mesenchymal stem cells; mitochondria; replicative senescence

DOI:  https://doi.org/10.3390/antiox14040446
J Alzheimers Dis Rep. 2025 Jan-Dec;9:9 25424823251329188

Alzheimer's disease and the immune system: A comprehensive overview with a focus on B cells, humoral immunity, and immunotherapy.

Ladan Gol Mohammad Pour Afrakoti, Sanam Daneshpour Moghadam, Pezhman Hadinezhad.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder and the major cause of dementia. Amyloid-β (Aβ) and tau aggregation, mitochondrial dysfunction, and microglial dysregulation are key contributors to AD pathogenesis. Impairments in the blood-brain barrier have unveiled the contribution of the immune system, particularly B cells, in AD pathology. B cells, a crucial component of adaptive immunity, exhibit diverse functions, including antigen presentation and antibody production. While their role in neuroinflammatory disorders has been well-documented, their specific function in AD lacks adequate data. This review examines the dual role of the B cells and humoral immunity in modulating brain inflammation in AD and explores recent advancements in passive and active immunotherapeutic strategies targeting AD pathobiology. We summarize preclinical and clinical studies investigating B cell frequency, altered antibody levels, and their implications in neuroinflammation and immunotherapy. Notably, B cells demonstrate protective and pathological roles in AD, influencing neurodegeneration through antibody-mediated clearance of toxic aggregates and inflammatory activation inflammation. Passive immunotherapies targeting Aβ have shown potential in reducing amyloid plaques, while active immunotherapies are emerging as promising strategies, requiring further validation. Understanding the interplay between B cells, humoral immunity, microglia, and mitochondrial dysfunction is critical to unraveling AD pathogenesis. Their dual nature in disease progression underscores the need for precise therapeutic interventions to optimize immunotherapy outcomes and mitigate neuroinflammation effectively.

Keywords:  Alzheimer's disease; B cell; adaptive immunity; amyloid-β; immunotherapy; tau

DOI:  https://doi.org/10.1177/25424823251329188
Brain Res Bull. 2025 Apr 30. pii: S0361-9230(25)00177-7. [Epub ahead of print] 111365

Activation of spinal PGC-1α regulates microglial polarization through a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome in neuropathic pain.

Qingling Xu, Qiulin Zhu, Guoxu Ling, Tonghong Huang, Tingting Su, Yanhua Chen, Yubo Xie, Yu Zhong.

   BACKGROUND: An imbalance in microglial polarization plays an important role in the pathogenesis of neuropathic pain. PPARγ coactivator-1α (PGC-1α), a master coregulator of gene expression in mitochondrial biogenesis, is related to microglial polarization. However, the underlying mechanism involved is poorly understood.The aim of the present study was to explore the role of PGC-1α in regulating microglial polarization through a feedback loop between reactive oxygen species (ROS)-mediated mitochondrial dysfunction and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of chronic constriction injury (CCI).
METHODS: we quantified pain behaviour after CCI; analysed the localization of PGC-1α and the changes in the expression of CD68 (an M1 microglial marker)/IBA1 and ARG1 (an M2 microglial marker)/IBA1 in the dorsal horn (DH) via immunofluorescence. Western blotting and immunofluorescence were used to examine the expression of target proteins. Quantitative real-time PCR (qPCR) was used to investigate the mitochondrial DNA copy number (mtDNA). ROS production was measured via dihydroethidium (DHE). SOD activity and the MDA content were measured via SOD and MDA assay kits, respectively. In addition, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA).
RESULTS: The results revealed ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome activation, microglia phenotype from the M2 to the M1 phenotype in the CCI rats.Interesting, ROS-mediated mitochondrial dysfunction is one of the critical mediators of NLRP3 inflammasome activation.NLRP3 inflammasome in turn cause ROS production and mitochondrial dysfunction, suggesting for the first time a feedback loop between ROS-mediated mitochondrial dysfunction and NLRP3 inflammasome in the neuropathic pain.The activation of PGC-1α shifts the microglial phenotype via the modulation of a feedback loop between ROS-mediated mitochondrial dysfunction and the NLRP3 inflammasome.
CONCLUSIONS: These findings indicate that activation of PGC-1α could be a potential therapeutic approach to ameliorate neuropathic pain.

Keywords:  Microglia polarization; NLRP3 inflammasome; Neuroinflammation; PGC-1α; ROS

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111365
J Sci Food Agric. 2025 May 01.

Ketoglutaric acid treatment enhances the antioxidant status of broccoli sprouts.

Tomasz Piechowiak, Maciej Balawejder, Piotr Antos.

   BACKGROUND: Ketoglutaric acid (α-KGA) is a dicarboxylic ketoacid with strong biological activity, whose main role in eukaryotic organisms is to participate in the Krebs cycle. In the present study, we tested whether the application of α-KGA to edible sprout culture would increase the content of low-molecular-weight antioxidants by improving their mitochondrial activity. For this purpose, broccoli sprouts were treated at the beginning of germination with an aqueous solution of α-KGA, at various concentrations (0, 0.1, 1, and 10 mmol L-1), which after 5 days of germination were analyzed for markers of antioxidant status, oxidative stress, and energy metabolism.
RESULTS: We showed that α-KGA promotes the production of antioxidants, which was manifested by increased content of ascorbic acid, glutathione, and polyphenols, as well as higher expression of the relevant enzymes for the biosynthesis of these substances (galactono-1,4-lactone dehydrogenase, glutathione synthase, phenylalanine ammonia-lyase). Induction of antioxidant biosynthesis was associated with an increase in mitochondrial activity, as we observed both an increase in the expression of respiratory proteins (aconitase 1, H+-ATPase) as well as an increase in ATP levels, oxidation of NADH, and an accumulation of reactive oxygen species and a consequent increase in the expression of antioxidant enzymes (manganese superoxide dismutase, catalase).
CONCLUSION: The above results showed that the application of α-KGA to the culture medium can improve the antioxidant status of edible sprouts. However, the effect obtained largely depends on the concentration of α-KGA in the medium, which shows that the mechanism of α-KGA effect on sprouts is based on the phenomenon of hormesis. © 2025 Society of Chemical Industry.

Keywords:  antioxidants; broccoli sprouts; functional food; immunoblotting; oxidative stress; volatile compounds

DOI:  https://doi.org/10.1002/jsfa.14323
Front Cell Neurosci. 2025 ;19 1549265

Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.

Adhithiya Charli, Yuan-Teng Chang, Jie Luo, Bharathi Palanisamy, Emir Malovic, Zainab Riaz, Cameron Miller, Manikandan Samidurai, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy.

  Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, are highly vulnerable to mitochondrial stress; however, the cellular and molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is highly expressed in DAergic neurons and mediates apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKCδ signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cells to the mitochondrial complex-1 inhibitor tebufenpyrad (Tebu) induced PKCδ phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation. High-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKCδ translocates to the nucleus, colocalizing with Lamin B1. Electron microscopy also visualized nuclear membrane damage in Tebu-treated N27 cells. In silico analyses identified threonine site on Lamin B1 (T575) as a phosphorylation site of PKCδ. Interestingly, N27 DAergic cells stably expressing a PKCδ cleavage-resistant mutant failed to induce nuclear damage, PKCδ activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKCδ greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using the Lamin B1T575G phosphorylation mutant and PKCδ-ΔNLS-overexpressing N27 cells showed that PKCδ activation and translocation to the nuclear membrane are essential for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKCδ-/- mouse pups. Postmortem analyses of PD brains revealed significantly higher PKCδ activation, Lamin B1 phosphorylation, and Lamin B1 loss in nigral DAergic neurons compared to age-matched healthy controls, demonstrating the translational relevance of these findings. Collectively, our data reveal that PKCδ functions as a Lamin B1 kinase to disassemble the nuclear membrane during mitochondrial stress-induced neuronal death. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.

Keywords:  Lamin B1; PKCδ; Parkinson’s disease; mitochondria; mitochondrial complex-1 inhibitor; neurodegenerative diseases; nuclear membrane disassembly; tebufenpyrad

DOI:  https://doi.org/10.3389/fncel.2025.1549265
Antioxidants (Basel). 2025 Apr 18. pii: 490. [Epub ahead of print]14(4):

Cyanidin-3-O-Glucoside Mitigates Amyloid-Beta (1-42)-Induced Apoptosis in SH-SY5Y Cells by Regulating Ca2+ Homeostasis and Inhibiting Mitochondrial Dysfunction.

Chao Ma, Yu Nie, Donglei Zhang, Lulu Ran, Su Xu, Xun Ran, Junya Huang, Lingshuai Meng.

   BACKGROUND: Blueberry anthocyanin such as Cyanidin-3-O-glucoside may help prevent Alzheimer's disease. We aimed to investigate the preventive and therapeutic effects of Cyanidin-3-O-glucoside against Aβ1-42-induced apoptosis of SH-SY5Y cells as well as the underlying mechanisms.
METHODS: Cell viability and intracellular and mitochondrial reactive oxygen species were detected by MTT, a reactive oxygen species detection kit, and a MitoSOX red mitochondrial superoxide indicator. The mitochondrial membrane potential, intracellular calcium ion content, and adenotriphophate (ATP) were identified via a mitochondrial membrane potential detection kit, calcium ion detection kit, and ATP detection kit, and apoptosis was detected via flow cytometry. Transcription of apoptosis-related genes was detected using real-time fluorescence quantitative polymerase chain reaction, and expression of apoptosis-related proteins was identified using Western blot.
RESULTS: We found that Cyanidin-3-O-glucoside could downregulate the expression of cytochrome c, caspase 9, caspase 3, and other genes and proteins, which consequently reduced the rate of apoptosis. Additionally, it could upregulate Bcl-2 gene and protein expression, downregulate Bax gene and protein expression, regulate mitochondrial membrane permeability and calcium-release channels, reduce calcium influx into mitochondria, maintain intracellular calcium ion levels, reduce intracellular levels of reactive oxygen species and increase ATP levels, maintain the mitochondrial membrane potential at a normal level, maintain normal mitochondrial functioning, and prevent apoptosis.
DISCUSSION: Taken together, Cyanidin-3-O-glucoside showed dose-dependent preventive and therapeutic effects against Aβ1-42-induced apoptosis of SH-SY5Y cells.
CONCLUSIONS: Cyanidin 3-O-glucoside showed a better preventive effect than therapeutic effect against Aβ1-42-induced apoptosis in SH-SY5Y cells.

Keywords:  Ca2+ homeostasis; Cyanidin-3-O-glucoside; apoptosis; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/antiox14040490
Theranostics. 2025 ;15(11): 4909-4929

Mitochondria-targeting natural product rhein conjugated with dichloroacetate as the dual inhibitor of glycolysis and oxidative phosphorylation to off energize cancer cells and induce ROS storm.

Zhili Zhang, Shiming Tang, Minghui Qi, Hongyang Zhao, Meng Wu, Shi-Wen Huang.

  Rationale: Metabolic reprogramming emerges as a remarkable hallmark of cancer cells and exhibits potential in the development of metabolic modulators. Numerous small-molecule inhibitors mainly target reversing the dominant-glycolysis pathway. However, energy metabolic adaptation that facilitates the alternation of metabolic phenotypes from glycolysis to oxidative phosphorylation (OXPHOS) undermines treatment efficacy. Thus, small molecular therapeutic agents, concurrently cutting off the cellular energy metabolism of glycolysis and OXPHOS and trigger oxidative stress damage, hold promise for cancer therapy. Methods: Herein, natural product rhein with the capacity of mitochondria-targeting was conjugated with pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) to form a multifunction small molecule drug Rhein-DCA conjugate. The ATP production inhibition, oxidative stress damage and antitumor efficacy of Rhein-DCA conjugate were evaluated both in vitro and in vivo. Results: Rhein unit not only led to the effective accumulation of Rhein-DCA conjugate in mitochondria, but also promoted the binding of DCA and PDK1, enhancing typical inhibition of glycolysis by DCA via PDK-PDH axis. Unlike classical PDK inhibitors, which restrained glycolysis and restored OXPHOS, rhein within the conjugate further suppressed mitochondrial respiratory chain complex and induced sustained opening of mitochondrial permeability transition pore, destroying intractable OXPHOS. Importantly, rhein component in the conjugate elevated the reactive oxygen species (ROS) level to further disrupt OXPHOS, and thus ROS triggered the release of damage associated molecular patterns. Simultaneously, the conjugate weakened lactate-mediated immunosuppression by reducing lactate levels in the tumor microenvironment. Eventually, the polarization state of tumor-associated macrophages could be effectively reversed following oral administration. Conclusion: This study designed a small-molecule dual-inhibitor of glycolysis and OXPHOS to circumvent metabolic adaptations and simultaneously induce immunogenic cell death for macrophages repolarization, thereby synergistically promoting antitumor efficacy.

Keywords:  glycolysis; immunogenic cell death; mitochondria-targeting; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.7150/thno.107812
Pharmacol Res Perspect. 2025 Jun;13(3): e70105

Glutathione Decreases Parkinsonism-Induced Ferroptosis and Oxidative Stress Through the Inhibition of the TRPM2 Channel in Neuronal Cells.

Elif Güzel, Ayşe Arzu Sayın Şakul, Mustafa Nazıroğlu.

  Parkinson's disease (PD) is the most prevalent neurodegenerative disease. Previously, it was believed that aberrant iron metabolism, leading to ferroptosis due to glutathione (GSH) depletion, excessive Ca2+ influx, mitochondrial (mROS), and cytosolic (cROS) free reactive oxygen species in the brain, was a contributing factor to PD. ADP-ribose (ADPR), mROS, and cROS activate the TRPM2 cation channel. It is yet unclear how TRPM2 contributes to the development of neuronal damage induced by the rise in ferroptosis in PD. Our aim in this study was to examine the function of TRPM2 and the protective effect of GSH in the dopaminergic human SH-SY5Y neuronal cells that had been exposed to 1-methyl 4-phenylpyridinium (MPP) to produce parkinsonism. The SH-SY5Y cells were divided into six groups: control, MPP, MPP + erastin, MPP + erastin + ferrostatin-1, MPP + erastin + glutathione (GSH), and MPP + erastin + TRPM2 blocker (ACA). In the MPP and MPP + erastin groups, the concentrations of Ca2+, ADPR-induced TRPM2 current density, mitochondrial membrane dysfunction, mROS, cROS, lipid peroxidation, mitochondrial Zn2+, cytosolic Zn2+, and cytosolic Fe2+ were increased, although glutathione peroxidase, GSH, cell viability, and cell number were decreased. The changes were higher in the MPP + erastin group than in MPP group only. However, their concentrations were modulated by the changes in the MPP + erastin + ferrostatin-1, MPP + erastin + GSH, and MPP + erastin + ACA groups. In conclusion, the increase in death and ferroptosis in parkinsonism (MPP)-induced SH-SY5Y cells was attributed to TRPM2 activation. By regulating cytosolic oxidant/antioxidant balance, GSH regulates TRPM2 channel activity and lowers neuronal death and ferroptosis.

Keywords:  Parkinson's disease; SH‐SY5Y cell death; TRPM2 channel; ferroptosis; glutathione

DOI:  https://doi.org/10.1002/prp2.70105
Antioxidants (Basel). 2025 Mar 25. pii: 384. [Epub ahead of print]14(4):

The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions.

Domenica Mallardi, Guglielmina Chimienti, Fatima Maqoud, Antonella Orlando, Simona Drago, Eleonora Malerba, Caterina De Virgilio, Hamid I Akbarali, Francesco Russo.

  Hydrogen sulfide (H2S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H2S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and inflammation. The aim of this study was to investigate the dose-dependent effects of exogenous H2S on mitochondrial functions and biogenesis in intestinal epithelial cells under non-stressed conditions. Using a Caco-2 monolayer model, we evaluated the impact of sodium hydrosulfide (NaHS) at concentrations ranging from 1 × 10-7 M to 5 × 10-3 M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H2S concentrations (1 × 10-7 M-1.5 × 10-3 M) enhance mitochondrial biogenesis through PGC-1α activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 × 10-3-5 × 10-3 M) impair mitochondrial function, induce oxidative stress, and promote apoptosis. These effects are associated with elevated reactive oxygen species (ROS) production, dysregulation of antioxidant enzymes, and COX-2-mediated inflammation. H2S-induced autophagy/mitophagy is a protective mechanism at intermediate concentrations but fails to mitigate mitochondrial damage at toxic levels. This study underscores the delicate balance between the cytoprotective and cytotoxic effects of exogenous H2S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders.

Keywords:  Caco-2 monolayer model; cytoprotection; gastrointestinal tract; hydrogen sulfide; mitochondria/metabolism; oxidation reduction

DOI:  https://doi.org/10.3390/antiox14040384
Antioxidants (Basel). 2025 Apr 20. pii: 497. [Epub ahead of print]14(4):

Role of Reactive Oxygen Species in Collagen-Induced Platelet Activation and the Protective Effects of Antioxidants.

Jin-Yi Han, Hideo Utsumi, Han-Young Chung.

  Collagen plays a crucial role in platelet activation and thrombosis, yet the underlying mechanisms involving reactive oxygen species (ROS) remain incompletely understood. This study investigated how collagen modulates ROS generation and platelet aggregation both in vitro and in vivo, as well as evaluating the protective effects of antioxidants. In vitro, collagen induced dose-dependent platelet aggregation and increased ROS generation, evidenced by the enhanced EMPO adduct formation detected via electron spin resonance (ESR). In vivo experiments demonstrated that collagen administration significantly accelerated CAT-1 decay, indicating elevated oxidative stress with a transient peak around 1 minute post-treatment. Furthermore, escalating collagen doses correlated with increased ROS generation and reduced survival rates in mice, underscoring collagen's impact on oxidative stress and thrombosis severity. Importantly, treatment with enzymatic antioxidants (superoxide dismutase, catalase) and non-enzymatic antioxidants (DMTU, Tiron, mannitol) significantly attenuated collagen-induced oxidative stress and improved animal survival. Collectively, these findings elucidate the pivotal role of ROS in collagen-induced platelet activation and thrombosis and highlight antioxidants as promising therapeutic candidates for preventing thrombotic disorders and managing cardiovascular risk.

Keywords:  collagen; in vivo ESR; platelet; spin-trapping; thrombosis

DOI:  https://doi.org/10.3390/antiox14040497
Biomolecules. 2025 Apr 14. pii: 580. [Epub ahead of print]15(4):

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.

Varshini V Suresh, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy.

  Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Keywords:  GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/biom15040580
Sci Rep. 2025 Apr 25. 15(1): 14501

Coenzyme Q10 protects keratinocytes against oxidation-induced energy stress as revealed by spatiotemporal analysis of cell energetics.

Roland Abi Nahed, Ali Hussein, Cécile Cottet-Rousselle, Alexandra Vogelsang, Francesco Aulicino, Imre Berger, Thomas Blatt, Julia M Weise, Uwe Schlattner.

  Coenzyme Q10 (Q10) plays a critical role in cellular energy conversion within the mitochondrial respiratory chain and offers protective effects against oxidative and metabolic stress. In this study, we investigated the impact of Q10 on the spatio-temporal patterns of cellular energetics in keratinocyte-derived HaCaT cells, utilizing the genetically-encoded FRET sensor AMPfret. Engineered from the AMP-activated protein kinase (AMPK), this sensor leverages endogenous affinities of the kinase that evolved to detect energy stress, specifically decreases in ATP/ADP and ATP/AMP ratios that pose a threat to cell survival. We successfully established HaCaT cells stably expressing AMPfret, validated their functionality by inducing energy stress with 2-deoxy-D-glucose, and demonstrated that Q10, together with high glucose conditions in culture, can enhance cellular energetics compared to low glucose controls. We then employed AMPfret to analyze the spatio-temporal response of HaCaT keratinocytes to Luperox (tert-butyl peroxide), a potent organic prooxidant, in the presence of varying intracellular levels of Q10. Preloading cells with Q10 was protective, slowing the speed and reducing the extend of the energy stress response. In contrast, preincubation with Simvastatin, an inhibitor of the mevalonate Q10 biosynthesis pathway, depleted cellular Q10 levels, accelerated the onset of energy stress, and led to early cell death as compared to controls. Under all conditions, AMPfret revealed cell-to-cell heterogeneity in energy stress at baseline and in the response to Luperox. Overall, tracking changes in energy state in time and at single-cell level allows further insights into the beneficial role of Q10 in enhancing cellular bioenergetics in skin cells, and a potential role of AMPK in mediating responses to altered Q10 levels.

Keywords:  Cellular bioenergetics; Coenzyme Q10; FRET sensor; HaCaT cells; Keratinocytes; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-025-98793-4
Genes Dis. 2025 Jul;12(4): 101437

Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.

Ye Hong, Ying Song, Wenjun Wang, Jinghui Shi, Xi Chen.

  Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.

Keywords:  Base editor; CRISPR-Cas9; Mitochondrial DNA; Neurodegenerative diseases; mitoTALENs; mitoZFNs

DOI:  https://doi.org/10.1016/j.gendis.2024.101437
Int Immunopharmacol. 2025 Apr 25. pii: S1567-5769(25)00675-7. [Epub ahead of print]156 114685

PICK1 overexpression ameliorates endotoxin-induced acute lung injury by regulating mitochondrial quality control via maintaining Nrf-2 stabilization through activating the PI3K/Akt/GSK-3β pathway and disrupting the E3 ubiquitin ligase adapter β-TrCP.

Meizi Qian, Yurun Zhu, Wen Lin, Huidan Lian, Yun Xia, Thomas Papadimos, Junlu Wang.

  Mitochondria are important targets for preventing oxidative damage during the progression of sepsis-induced lung injury. Numerous studies have pointed out that maintaining the stabilization of Nrf-2, thereby activating its transcription, may combat pathological inflammation by sustaining the integrity of mitochondrial function. Our previous study found that protein interaction with C-kinase 1 (PICK1) deficiency disrupts the physiological anti-inflammatory mechanism by affecting Nrf-2 transcription. However, whether PICK1 participates in mitochondrial quality control regulation through Nrf-2 has not been explored, and the underlying interaction between PICK1 and Nrf-2 has not been fully elucidated. We found that PICK1 decreased mitochondria-derived ROS, upregulated MnSOD activity in endotoxin-induced acute lung injury mice, improved mitochondrial membrane potential, and restored the damaged structure of mitochondria in LPS-stimulated macrophages. Through in-depth studies, we demonstrated that PICK1 maintains the stability of Nrf-2 by preserving mitochondrial dynamic equilibrium, facilitating mitochondrial biogenesis, and participating in mitophagy by activating the PI3K/AKT/GSK-3β pathway. PICK1 also inhibits the β-TrCP-mediated ubiquitination of Nrf-2. Thus, PICK1 offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation. Our study demonstrated the protective effects of PICK1 overexpression in endotoxin-associated ALI. PICK1 overexpression and the subsequent PI3K/AKT/Nrf-2/HO-1 pathway-dependent and E3 ubiquitin ligase adapter β-TrCP-mediated mitochondrial quality control contribute to lung repair, which offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation.

Keywords:  Endotoxin-related acute lung injury; Mitochondrial quality control; Nrf-2; PICK1; Β-TrCP

DOI:  https://doi.org/10.1016/j.intimp.2025.114685
J Intern Med. 2025 Apr 27.

Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes.

David Rizo-Roca, John D Henderson, Juleen R Zierath.

  Cardiometabolic diseases-including Type 2 diabetes and obesity-remain leading causes of global mortality. Recent advancements in metabolomics have facilitated the identification of metabolites that are integral to the development of insulin resistance, a characteristic feature of cardiometabolic disease. Key metabolites, such as branched-chain amino acids (BCAAs), ceramides, glycine, and glutamine, have emerged as valuable biomarkers for early diagnosis, risk stratification, and potential therapeutic targets. Elevated BCAAs and ceramides are strongly associated with insulin resistance and Type 2 diabetes, whereas glycine exhibits an inverse relationship with insulin resistance, making it a promising therapeutic target. Metabolites involved in energy stress, including ketone bodies, lactate, and nicotinamide adenine dinucleotide (NAD⁺), regulate insulin sensitivity and metabolic health, with ketogenic diets and NAD⁺ precursor supplementation showing potential benefits. Additionally, the novel biomarker N-lactoyl-phenylalanine further underscores the complexity of metabolic regulation and its therapeutic potential. This review underscores the potential of metabolite-based diagnostics and precision medicine, which could enhance efforts in the prevention, diagnosis, and treatment of cardiometabolic diseases, ultimately improving patient outcomes and quality of life.

Keywords:  biomarkers; cardiometabolic diseases; insulin resistance; metabolomics; therapeutic targets

DOI:  https://doi.org/10.1111/joim.20090
Brain Res Bull. 2025 Apr 28. pii: S0361-9230(25)00178-9. [Epub ahead of print] 111366

The interaction between metals and catecholamines: oxidative stress, DNA damage, and implications for human health.

Elena Cassera, Emanuele Ferrari, Davide A L Vignati, Andrea Capucciati.

  The interaction between metals and catecholamines plays a pivotal role in the generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage. ROS are linked to several diseases, including neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. This review examines how essential metals (iron, copper, zinc, manganese) and a few non-essential metal(loid)s (mercury, chromium, arsenic, aluminum, cadmium, and nickel) contribute to oxidative stress in the presence of catecholamines. In the presence of metals, catecholamines can cause oxidative DNA modification, possibly resulting in cell apoptosis, by taking part in redox reactions and oxidizing to the corresponding aminochrome with simultaneous ROS production. Essential metals are vital for physiological functions, but imbalances in their homeostasis can be harmful. Furthermore, non-essential metals, commonly encountered through environmental or occupational exposure, can exhibit significant toxicity. Previous studies on catecholamine-induced oxidative stress focused on copper and iron, but this review emphasizes the need to investigate other neurotoxic metals and expand existing knowledge on the interactions between metals, catecholamines, and DNA damage. Results from such research could help prioritizing the development of new assessment methods associated with adverse outcome pathways, to reliably predict harmful effects on human health, aiding in the development of therapeutical strategies. The present work will help to shed light on the interplay of metals, catecholamines, and DNA damage in different diseases hopefully fostering new research in this still understudied topic. Future research should investigate the molecular mechanisms through which these metals affect neuronal health and contribute to disease pathogenesis.

Keywords:  DNA damage; Oxidative stress; ROS; catecholamines; metals; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111366
Curr Med Chem. 2025 Apr 25.

Advanced Glycation End Products and Skin Autoimmune Disorders: Pathogenic Insights into Vitiligo, Bullous Pemphigoid, and Type 1 Diabetes Mellitus.

Geir Bjørklund, Leonard Gurgas, Tony Hangan.

  AGEs are molecules formed by nonenzymatic glycation of proteins, lipids, and nucleic acids, a process accelerated under hyperglycemic conditions such as DM1. These molecules interact with specific receptors, particularly the Receptor for AGEs (RAGE), triggering intracellular signaling cascades that promote oxidative stress through the generation of Reactive Oxygen Species (ROS) and activation of inflammatory pathways. A critical pathological mechanism involves the formation of neoantigens, modified self-proteins that elicit immune responses. Structural alterations caused by AGEs expose new epitopes or modify existing ones, making them targets for autoreactive T cells and autoantibodies. This mechanism is implicated in autoimmune skin diseases such as vitiligo and bullous pemphigoid. Oxidative stress plays a central role in these diseases, exacerbated by AGEs through the generation of ROS and depletion of antioxidants, leading to melanocyte destruction in vitiligo and tissue damage in bullous pemphigoid. In addition, hypoxia enhances ROS production, mitochondria, and other cellular systems contributing to oxidative stress. Emerging evidence suggests that hypoxia can be mitigated by oxygen nanobubbles. Targeting AGE formation and oxidative stress presents a promising approach for the management of autoimmune skin disorders in DM1. Therapeutic strategies targeting AGE formation, oxidative stress, and immune dysregulation show promise for managing autoimmune skin disorders in Type 1 Diabetes Mellitus (T1DM). AGE inhibitors, such as aminoguanidine and pyridoxamine, reduce non-enzymatic protein glycation, limiting AGE accumulation and inflammatory signaling. Antioxidants, including polyphenols, vitamins C and E, N-acetylcysteine, selenium, and hydrogen-rich water, help neutralize Reactive Oxygen Species (ROS), restoring oxidative balance. Combining AGE inhibitors and antioxidants may provide synergistic benefits by reducing oxidative stress and protein immunogenicity. Additionally, immune modulation therapies, such as Treg therapy and cytokine inhibitors, aim to restore immune tolerance and prevent autoimmune activation. Anti-TNF-α and IL-6 inhibitors offer targeted inflammation suppression, while RAGE antagonists mitigate AGE-induced immune dysregulation. This study aims to explore the role of Advanced Glycation End products (AGEs) in the pathogenesis of autoimmune skin disorders associated with type 1 Diabetes Mellitus (DM1) and to evaluate potential therapeutic strategies targeting AGE formation and oxidative stress.

Keywords:  Advanced glycation end products; bullous pemphigoid; immune dysregulation; therapeutic interventions.; type 1 diabetes mellitus; vitiligo

DOI:  https://doi.org/10.2174/0109298673374335250410074811
FASEB J. 2025 May 15. 39(9): e70575

Aging and Lifestyle Modifications for Preventing Aging-Related Diseases.

Qiao Li, Heng Zhang, Nanyin Xiao, Guangyu Liang, Yan Lin, Xiao Yang, Jiankun Yang, Zonghao Qian, Yangguang Fu, Cuntai Zhang, Anding Liu.

  The pathogenesis of various chronic diseases is closely associated with aging. Aging of the cardiovascular system promotes the development of severe cardiovascular diseases with high mortality, including atherosclerosis, coronary heart disease, and myocardial infarction. Similarly, aging of the nervous system promotes the development of neurodegenerative diseases, such as Alzheimer's disease, which seriously impairs cognitive function. Aging of the musculoskeletal system is characterized by decreased function and mobility. The molecular basis of organ aging is cellular senescence, which involves multiple cellular and molecular mechanisms, such as impaired autophagy, metabolic imbalance, oxidative stress, and persistent inflammation. Given the ongoing demographic shift toward an aging society, strategies to delay or reduce the effects of aging have gained significance. Lifestyle modifications, such as exercise and calorie restriction, are now recognized for their anti-aging effects, their capacity to reduce modification, their potential to prolong lifespan, and their capacity to lower the risk of cardiovascular disease. This review elucidates the molecular mechanisms and application significance of various anti-aging approaches at the molecular level, based on research progress in aging. It aims to provide a reference for the prevention and treatment of age-related diseases in progressively aging societies.

Keywords:  aging; aging‐related diseases; cellular senescence; lifestyle modifications

DOI:  https://doi.org/10.1096/fj.202402797RR
Exp Neurol. 2025 Apr 24. pii: S0014-4886(25)00136-0. [Epub ahead of print]390 115272

Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques.

Sarah Kaye, Andrew Gold, Da Lin, Min Chen, Jiangjiang Zhu, Jie Gao.

  Hypercholesterolemia is a recognized comorbidity of Alzheimer's disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APPNL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APPNL-G-F;LDLR-/- (ALKO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a control diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.

Keywords:  Alzheimer's disease; Amyloid beta; Hypercholesterolemia; Microglia

DOI:  https://doi.org/10.1016/j.expneurol.2025.115272
medRxiv. 2025 Apr 12. pii: 2025.04.09.25325473. [Epub ahead of print]

Saliva and Blood Cell-Free mtDNA Reactivity to Acute Psychosocial Stress.

Caroline Trumpff, David Shire, Jeremy Michelson, Natalia Bobba-Alves, Temmie Yu, Richard P Sloan, Robert-Paul Juster, Michio Hirano, Martin Picard.

Human blood contains cell-free mitochondrial DNA (cf-mtDNA) that dynamically increases in concentration in response to acute mental stress. Like other neuroendocrine stress markers, we previously found that cf-mtDNA is also detectable in saliva, calling for studies examining saliva cf-mtDNA reactivity to mental stress. In healthy women and men from the MiSBIE (Mitochondrial Stress, Brain Imaging, and Epigenetics) study (n=68, 66% women), a brief socio-evaluative stressor induced a striking 280% or 2.8-fold increase in saliva cf-mtDNA concentration within 10 minutes (g=0.55, p<0.0001). In blood drawn concurrently with saliva sampling, stress increased cf-mtDNA by an average 32% at 60 min in serum (g=0.20), but not in anticoagulated plasma where cf-mtDNA decreased by 19% at 60 min (g=0.25). Examining the influence of mitochondrial health on cf-mtDNA reactivity in participants with rare mitochondrial diseases (MitoD), we report that a subset of MitoD participants exhibit markedly blunted saliva cf-mtDNA stress reactivity, suggesting that bioenergetic defects within mitochondria may influence the magnitude of saliva, and possibly blood cf-mtDNA responses. Our results document robust saliva cf-mtDNA stress reactivity and provide a methodology to examine the psychobiological regulation of cell-free mitochondria in future studies.

DOI: https://doi.org/10.1101/2025.04.09.25325473
Nutrients. 2025 Mar 10. pii: 969. [Epub ahead of print]17(6):

Exercise Mimetics in Aging: Suggestions from a Systematic Review.

Emiliana Giacomello, Claudio Nicoletti, Marta Canato, Luana Toniolo.

  Background/Objectives: Growth in the aging world population is accompanied by an increase in comorbidities, profoundly impacting the quality of life of older people. This development has motivated a large effort to investigate the mechanisms underlying aging and the search for countermeasures. The most investigated strategies envisage the control of diet and physical exercise, which exploit both common and distinct mechanisms to promote health. Since the application of nutritional and exercise protocols to aged persons introduces several issues due to their disabled state, some strategies have been developed. The nutritional approach exploits a wide range of compounds, including calorie restriction mimetics, supplements, antioxidants, and others. In the context of exercise, in recent years, molecules able to provide similar effects to exercise, the so-called exercise mimetics, have been developed. Methods: To have a better perspective on exercise mimetics and their connection with nutrition, we performed a systematic search of the PubMed and Scopus databases using the term "exercise mimetics". Results: In total, 97 research articles were selected and discussed. The present review provides evidence of the presence of multiple exercise-mimetic compounds and physical strategies that can target metabolic pathways, oxidative stress defense mechanisms, or myokine modulation. Conclusions: Interestingly, this review highlights that an important number of exercise mimetics are represented by products of natural origin and supplements assimilable with diet. This evidence provides a further link between exercise and nutrition and confers a central role on nutrition in the context of exercise mimetics.

Keywords:  aging; exercise; exercise mimetics; health span; lifespan; metabolism; myokines; natural compounds; nutrient sensing pathway

DOI:  https://doi.org/10.3390/nu17060969
Curr Mol Med. 2025 Apr 25.

Exercise Alleviates Atherosclerosis Through the Modulation of the NLRP3 Inflammasome.

Xuan Liu, Shujuan Hu, Xianwang Wang, Yuqing Ding.

  Atherosclerosis (AS) is a chronic inflammatory disease closely associated with endothelial dysfunction and oxidative stress. The NOD-like receptor protein 3 (NLRP3) inflammasome, a key regulator of inflammatory responses, can exacerbate the progression of AS when activated. Growing evidence suggests that exercise, as a non-pharmacological intervention, can alleviate the progression of AS by modulating the activity of NLRP3 inflammasome. This review discusses how exercise influences the development of AS through the regulation of NLRP3 inflammasome and the underlying molecular mechanism. This study introduces the structure and activation mechanisms of NLRP3 inflammasome, as well as its role in AS. And summarizes how exercise can ameliorate endothelial dysfunction, regulate lipid metabolism, and suppress oxidative stress and inflammation by affecting the expression and activity of NLRP3 inflammasome, thereby exerting a beneficial impact on AS. Additionally, we explore the effects of exercise on the downstream inflammatory cytokines of NLRP3 inflammasome and how this regulation could help to slow the progression of AS. These findings underscore the therapeutic relevance of exercise in the prevention and treatment of AS. It provides new insights into the role of exercise interventions in the management of AS and lays a theoretical foundation for the development of innovative treatment strategies for cardiovascular disease. Given that the NLRP3 inflammatome plays an important role in the pathogenesis and treatment of AS, exercise therapy strategies targeting the NLRP3 inflammatome will help promote the development of precision medicine for AS.

Keywords:  NLRP3 inflammasome; atherosclerosis; endothelial dysfunction; exercise; lipid metabolism.; oxidative stress

DOI:  https://doi.org/10.2174/0115665240368171250419113225
Eur J Pharmacol. 2025 Apr 29. pii: S0014-2999(25)00445-5. [Epub ahead of print] 177691

Molecular Mechanisms and Therapeutic Perspectives of Luteolin on Diabetes and Its Complications.

Qingzhi Liang, Xiaoqin Liu, Xin Xu, Zhengtao Chen, Ting Luo, Yi Su, Chunguang Xie.

   BACKGROUND: Extensive preclinical studies have established luteolin, a flavonoid with potent antidiabetic activity, as a therapeutic candidate for preventing and managing various diabetic complications including cardiomyopathy, nephropathy, and osteopathy. This systematic review evaluates current evidence regarding luteolin's antidiabetic potential.
AIM OF THE STUDY: This study evaluates luteolin's efficacy in diabetes management through evidence synthesis, while critically assessing current research challenges and translational opportunities.
METHODS: A comprehensive literature search was conducted across Pubmed, Embase, Web of Science, and Google Scholar databases, encompassing articles published between 2000-2024.
RESULTS: Luteolin is a naturally occurring flavonoid that has strong antidiabetic properties. It regulates intestinal microenvironmental homeostasis, lipogenesis and catabolism, and the absorption of carbohydrates. It also modulates nine diabetic complications by reducing inflammation, oxidative stress, apoptosis, and autophagy. Luteolin's potential nutritional and physiological benefits notwithstanding, attention must be directed immediately to its bioavailability, innovative formulations, safety assessment, synergistic effects, and optimal dosage and time for supplementation. In particular, clinical studies are needed to validate efficacy and safety and provide a reliable scientific basis.
CONCLUSION: Luteolin may act as a pleiotropic molecule targeting multiple signaling cascades to exert antidiabetic bioactivity.

Keywords:  Diabetes mellitus; Diabetic complication; Luteolin; Traditional Chinese medicine monomer

DOI:  https://doi.org/10.1016/j.ejphar.2025.177691