bims-mistre 2025-10-05 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–10–05
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondria as a Therapeutic Target in Metabolic Disorders.
GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.
GDF15 attenuates myocardial infarction-induced injury by preserving mitochondrial function and suppressing oxidative stress.
MitoQ reduces senescence burden in Doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage.
Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.
Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.
Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review).
Molecular Mechanisms of cGAS-STING Axis and Mitochondrial Dysfunction-Related Diseases in Humans: A Comprehensive Review.
Reproductive aging in biological females: mechanisms and immediate consequences.
Exploratory study of the dysregulation of age-related changes in neural/glial antigen 2 and neuroinflammation markers in individuals with major depression.
Interconnection between gut microbial metabolites and mitochondrial ROS production: implications for cellular health.
FGF21 maintains redox homeostasis and promotes neuronal survival after traumatic brain injury by targeting SLC25A39-mediated mitochondrial GSH transport.
Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights.
Systematic review and meta-analysis of antioxidants with or without exercise training improving muscle condition in older adults.
The stress-responsive cytokine GDF-15 and sarcopenia: A systematic review and meta-analysis on aging muscle decline.

Mini Rev Med Chem. 2025 Sep 29.

Mitochondria as a Therapeutic Target in Metabolic Disorders.

Youde Cai, Fang Gan, Yunzhi Chen, Qiansong He, Wei Chen, Zhongyong Peng, Ling Gong.

  Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.

Keywords:  Mitochondria; bioenergetics; cellular signaling; metabolism; redox biology; therapeutic target.

DOI:  https://doi.org/10.2174/0113895575403490250917111723
Exp Mol Med. 2025 Oct 01.

GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.

Jinyoung Kim, Annie Zhao, Seo Hyun Park, Jaeseok Han, Deok-Hyeon Cheon, Sang-Hyeon Ju, Yoonhyuk Jang, Kon Chu, Hyung Jin Choi, Jiyoon Kim, Myung-Shik Lee.

Growth differentiation factor 15 (GDF15) induces weight loss and increases sympathetic activity through its receptor GFRAL. Given that RET, a GFRAL coreceptor, influences neuronal growth, we studied whether GDF15 can induce the development or growth of sympathetic neurons, in addition to its effect on sympathetic activity. Here we we used GDF15-transgenic and Gdf15-knockout mice to explore the role of GDF15 in the development and activity of sympathetic neurons. GDF15-transgenic mice exhibited increased surface area and volume of sympathetic neurite in adipose tissues. Furthermore, these mice showed heightened energy expenditure, thermogenesis, cold tolerance and an elevated sympathetic response to hypoglycemia. GFRAL was expressed in sympathetic ganglion cells, which was enhanced by GDF15. RET and its downstream signaling molecules such as AKT, ERK and CREB were activated in the sympathetic ganglia by transgenic expression of GDF15 in vivo or treatment with GDF15 in vitro, an leading to increased expression of genes related to thermogenesis, neurite growth or extension and catecholamine synthesis. An ex vivo treatment of sympathetic ganglia with GDF15 also promoted neurite growth and extension. By contrast, Gdf15-knockout mice showed opposite phenotypes, underscoring the physiological role of GDF15 in the development and activity of the sympathetic nervous system. These findings indicate that GDF15 regulates not only the sympathetic activity but also the development or growth of sympathetic neurons through GFRAL expressed in sympathetic ganglion cells, which could contribute to energy expenditure and weight loss. The modulation of GDF15 could be a therapeutic option against diseases or conditions associated with dysregulated sympathetic activity.

DOI: https://doi.org/10.1038/s12276-025-01543-9
Eur J Med Res. 2025 Sep 29. 30(1): 903

GDF15 attenuates myocardial infarction-induced injury by preserving mitochondrial function and suppressing oxidative stress.

Xiaogang Yuan, Cheng Wang, Haiyan Zhu.

  Myocardial infarction, a serious cardiovascular disease, is still a major cause of morbidity and mortality worldwide. Growth differentiation factor-15, a stress-responsive cytokine, has been involved in cardiac pathophysiology, but its exact role in myocardial infarction remains controversial. This study aimed to clarify the mechanisms underlying the cardioprotective effects of GDF-15 in myocardial infarction. By using a combination of in vivo and in vitro methods, including immunofluorescence staining, echocardiography, RNA sequencing, and high-resolution respirometry, we showed that GDF-15 expression is significantly upregulated in infarcted myocardium and its deficiency aggravates cardiac injury. Mechanistically, GDF-15 deficiency impairs mitochondrial function and energy metabolism under hypoxic stress, as evidenced by changes in mitochondrial membrane potential and respiratory parameters. Moreover, we identified that GDF-15 suppresses hypoxia-induced reactive oxygen species generation through activation of the AMPK signaling pathway. Therapeutic administration of exogenous GDF-15 reduces myocardial injury, hypoxic stress, and fibrosis after myocardial infarction, suggesting its potential as a therapeutic target. These findings collectively demonstrate that GDF-15 plays a crucial role in cardiac protection during myocardial infarction by regulating mitochondrial function, energy metabolism, and oxidative stress. Our results provide novel insights into the molecular mechanisms of GDF-15-mediated cardioprotection and suggest its potential as a therapeutic intervention for myocardial infarction. Future studies should focus on translational research to evaluate the clinical efficacy of GDF-15-based therapies in myocardial infarction patients.

Keywords:  GDF15; Mitochondrial function; Myocardial infarction; Oxidative stress

DOI:  https://doi.org/10.1186/s40001-025-03144-8
Am J Physiol Heart Circ Physiol. 2025 Sep 30.

MitoQ reduces senescence burden in Doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage.

Hossein Abdeahad, Denisse G Moreno, Samuel Bloom, Lucas Norman, Lisa A Lesniewski, Anthony J Donato.

  Cardiovascular toxicity is one of the adverse consequences of chemotherapy, limiting its therapeutic application. Chemotherapeutics, such as doxorubicin (DOXO), induce endothelial dysfunction via genotoxic effects, and reactive oxygen species (ROS) and mitochondrial ROS (mtROS) generation. These mechanisms increase DNA damage and cellular senescence, a persistent cell cycle arrest promoting inflammation, which elevates future cardiovascular disease risk. The adverse impact of DOXO on endothelial function can be mitigated by the mitochondria-targeted antioxidant, MitoQ; however, its precise protective mechanism in endothelial cells (ECs) remains unclear. The present study hypothesizes that co-treating ECs with MitoQ and DOXO attenuates DOXO-induced mtROS, thereby reducing DNA damage, senescence, and inflammation. Mitochondrial superoxide levels, mitochondrial mass, DNA damage, and cellular senescence were assessed in human umbilical vein ECs (HUVECs) 48 hours after DOXO and/or MitoQ treatment. DOXO treatment increased mtROS production and reduced mitochondrial mass compared to the vehicle group. Co-treatment with MitoQ decreased mtROS production and preserved mitochondrial mass compared to DOXO alone. MitoQ Co-treatment prevented senescence induction in DOXO-treated HUVECs, evidenced by preventing increased mRNA expression for senescence markers and senescence-associated beta-galactosidase (SA-ꞵgal) activity, alongside higher cell proliferation (BrdU incorporation). Additionally, MitoQ co-treatment reduced DNA damage and telomere dysfunction (DNA damage signaling at telomeres) compared to DOXO alone. Collectively, these data suggest mtROS drives cellular senescence in ECs through increased DNA damage and telomere dysfunction. These findings provide insight into mechanisms underlying DOXO-induced endothelial dysfunction and support mitochondrial-targeted antioxidant treatment as a potential therapeutic to mitigate chemotherapy-induced cardiovascular toxicity.

Keywords:  Cardiovascular toxicity; Doxorubicin; Endothelial cell senescence; MitoQ; Mitochondrial ROS

DOI:  https://doi.org/10.1152/ajpheart.00568.2025
Neural Regen Res. 2025 Sep 29.

Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.

Tingting Fu, Xinyi Chen, Shuting Zhang, Ying Fu, Lin Huang, Wandi Xiong.

   ABSTRACT: The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; heteroplamy; mitochondrial DNA; mitochondrial DNA mutation; mitochondrial genome; mitochondrial haplogroup; mitochondrial homeostasis; neurodegenerative diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00495
bioRxiv. 2025 Sep 28. pii: 2025.09.25.678523. [Epub ahead of print]

Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.

Arnaud Tauffenberger, Payton J Netherland, Hubert Fiumelli, Joshua D Meisel, Frank C Schroeder, Pierre Magistretti.

Lactate has emerged as a key metabolite involved in multiple physiological processes, including memory formation, immune response regulation, and muscle biogenesis. However, its role in aging and cellular protection remains unclear. Here, we show that lactate promotes longevity in C. elegans through a mechanism that requires early-life intervention, indicating a hormetic priming effect. This pro-longevity action depends on its metabolic conversion via LDH-1 and NADH, which drives redox-dependent metabolic reprogramming. Multi-omics approaches revealed that lactate induces early-stage metabolic adaptations, with a strong modulation of lipid metabolism, followed by late-life transcriptional remodeling. These shifts are characterized by enhanced stress response pathways and suppression of energy- associated metabolic processes. Our genetic screening identified sir-2.1 /SIRT1 and rict- 1/ RICTOR as essential for lactate-mediated lifespan extension. Our findings establish lactate as a pro-longevity metabolite that couples redox signaling with lipid remodeling and nutrient- sensing pathways. This work advances our understanding of lactate's dual role as a metabolic intermediary and geroprotector signaling molecule, offering insights into therapeutic strategies for age-related metabolic disorders.

DOI: https://doi.org/10.1101/2025.09.25.678523
Int J Mol Med. 2025 Dec;pii: 215. [Epub ahead of print]56(6):

Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review).

Yang Yu, Han Yapeng, Zelin Liu, Lei Fang, Jianuo Li, Yifeng Luan, Wenzhong Li, Huifang Cong, Xiuhong Wu.

  Perimenopause represents a key transition from a reproductive to non‑reproductive state in women, characterized by physiological and psychological changes. Mood disturbances during this period, such as depression, anxiety and cognitive decline, are increasingly understood as complex neuroendocrine and metabolic disorders. Mitochondrial homeostasis carries out a key role in the pathophysiology of these affective symptoms. Disruptions in mitochondrial biogenesis, mitophagy and calcium regulation contribute to synaptic dysfunction and neuroimmune changes. These mitochondrial alterations interact with inflammatory pathways and hormonal signals, exacerbating neuropsychiatric symptoms. A more comprehensive understanding of the molecular mechanisms of mitochondrial dysfunction in menopausal mood disorders unveils potential therapeutic strategies, including mitochondria‑targeted antioxidants, hormone replacement therapy, and lifestyle interventions designed to restore mitochondrial integrity and cerebral bioenergetic function.

Keywords:  estrogen deficiency; mitochondrial dysfunction; mood disorders; perimenopause

DOI:  https://doi.org/10.3892/ijmm.2025.5656
Curr Neuropharmacol. 2025 Sep 25.

Molecular Mechanisms of cGAS-STING Axis and Mitochondrial Dysfunction-Related Diseases in Humans: A Comprehensive Review.

Xingtong Shen, Hantao Chen, Jishan Zheng, Yunyan Ma, Zhengzhen Tang, Hongqin Sun, Qian Zhang, Jidong Zhang, Tao Song.

  Mitochondria play a critical role in immune cell differentiation, activation, and the regulation of innate immune responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a key mediator of cytosolic DNA sensing and contributes to a broad spectrum of pathological processes, including infectious diseases, sterile inflammation, cancer, and autoimmune disorders. STING is activated in response to cytosolic DNA during infection and can restrict translation in RNA virus-infected cells as part of the innate immune response. Studies have shown that mitochondrial dysfunction, particularly the release of mitochondrial DNA (mtDNA), can act as a potent trigger of cGAS-STING signaling, linking mitochondrial damage to immune activation. Additionally, this pathway intersects with autophagy, metabolic regulation, and cell death mechanisms. This comprehensive review summarizes current advances in understanding the cGAS-STING axis and mtDNA release in the context of mitochondrial dysfunction, with a focus on their roles in disease pathogenesis and potential as therapeutic targets. We highlight recent progress in the development of targeted interventions and emphasize the importance of elucidating the regulatory mechanisms underlying STING activation in various pathological conditions, including neuroinflammation, cancer, ischemia/reperfusion injury, and autoimmune diseases.

Keywords:  autoimmune disorder.; cGAS-STING axis; ischemia/reperfusion injury; mitochondrial dysfunction; molecular mechanisms

DOI:  https://doi.org/10.2174/011570159X388747250830161230
Front Endocrinol (Lausanne). 2025 ;16 1658592

Reproductive aging in biological females: mechanisms and immediate consequences.

Yasin Ali Muhammad.

  Reproductive aging is a dynamic, systemic process that encompasses more than the decline in ovarian function. It involves coordinated changes across neuroendocrine, immune, metabolic, and mitochondrial systems. Central to this transition is the depletion of ovarian follicles, leading to reduced estradiol and progesterone production and subsequent disruption of the hypothalamic-pituitary-gonadal (HPG) axis. This hormonal shift remodels hypothalamic signaling networks - particularly those involving kisspeptin, neurokinin B (NKB), and GABA - driving alterations in gonadotropin-releasing hormone (GnRH) pulsatility, vasomotor symptoms (VMS), and loss of reproductive cycling. Simultaneously, chronic inflammation, oxidative stress, and mitochondrial dysfunction further accelerate both ovarian and neural aging. Estrogen receptor subtypes (ERα and ERβ) play critical and region-specific roles in mediating tissue responses to hormonal withdrawal, contributing to variability in symptom expression and therapeutic outcomes. Genetic, cultural, and environmental factors - such as diet, endocrine disruptors, and APOE genotype - further influence the trajectory and severity of menopause-related changes. Emerging treatments, including neurokinin receptor antagonists and ERβ-selective modulators, offer targeted alternatives to conventional hormone therapy. This review frames menopause not as a singular endocrine endpoint but as a neuroimmune transition, highlighting the need for mechanistic insight and personalized therapeutic approaches to improve health outcomes during reproductive aging.

Keywords:  aging; endocrine system; hypothalamas; menopause (estrogen withdrawal); ovarian follicle cells

DOI:  https://doi.org/10.3389/fendo.2025.1658592
Brain Behav Immun Health. 2025 Nov;49 101107

Exploratory study of the dysregulation of age-related changes in neural/glial antigen 2 and neuroinflammation markers in individuals with major depression.

Javier Vargas-Medrano, Diana Sotelo, Guadalupe Vidal Martínez, Peter M Thompson.

  Aging involves the alteration of the central nervous system myelin, which is produced by oligodendrocytes. These cells originate from oligodendrocyte precursor [neural/glial antigen 2 (NG2)] cells, which are influenced by neuroinflammatory processes. Neuroinflammatory activity contributes to accelerated aging in individuals with mental illnesses such as major depressive disorder (MDD). This study was conducted to better understand the anti- and pro-neuroinflammatory changes associated with NG2 cells in aging individuals with MDD. Human postmortem dorsolateral prefrontal cortex samples were obtained from adults with MDD and normal controls (NCs) of different ages. Western blotting was performed to measure the protein levels of the oligodendrocyte progenitor cell marker NG2, the inflammatory markers interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and the anti-inflammatory neuronal viability marker B-cell lymphoma 2 (Bcl-2). Age-related changes in these markers were examined by simple linear regression. In NCs, the levels of NG2 and HGF increased linearly with age (p = 0.04 and p = 0.02, respectively), and the Bcl-2 level tended to follow the same trend (p = 0.08). The IL-1β and TNF-α levels were not significantly associated with age in NCs (p = 0.96 and p = 0.67, respectively). In the MDD group, a linear relationship with age was observed for the HGF level (p = 0.03) but not the NG2 (p = 0.23) or Bcl-2 (p = 0.92) level. Trends toward significant positive linear relationships with age were observed for the levels of IL-1β (p = 0.06) and TNF-α (p = 0.08). Our data suggest that brain aging is advanced in individuals with MDD in part due to increased neuroinflammation and reduced pro-survival protein levels and myelination potential.

Keywords:  B-Cell lymphoma 2; Brain; Depression; Hepatocyte growth factor; Neural/glial antigen 2; Neuroinflammation; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.bbih.2025.101107
Mol Cell Biochem. 2025 Sep 30.

Interconnection between gut microbial metabolites and mitochondrial ROS production: implications for cellular health.

Priyanka Gupta, Sumit Dutta, Krishanu Dutta, Piyush Bhattacharjee, Arjama Hazra, Rajiv Jash.

  Trillions of microbes inhabit the human gut and engage in diverse biological processes by secreting different metabolites. These metabolites influence mitochondrial function and produce ROS. This gut-mitochondrial communication plays a pivotal role in regulating cellular homeostasis, energy production, and oxidative stress management, all required for optimal health. Short-chain fatty acids, secondary bile acids, amines, and gaseous metabolites are major gut metabolites that aid in governing mitochondrial processes to facilitate effective energy production and avoid oxidative damage. In the case of damaged mitochondrial function, it can alter gut flora (dysbiosis), resulting in inflammation and assisting a number of diseases such as multiple sclerosis, Alzheimer's disease, IgA nephropathy, inflammatory bowel disease, and colorectal cancer. The gut-mitochondria axis is a multifaceted interaction that regulates a cell's energy homeostasis and provides novel therapeutic opportunities. Probiotics, prebiotics, dietary modifications, and metabolite therapies have the potential to restore gut-microbe balance, enhance mitochondrial function, and reduce oxidative stress. These measures have the potential for new treatments for many diseases by modulating the gut-mitochondria axis. This review surveys interactions among gut microbiota, mitochondrial ROS, and the gut-mitochondria axis, describing how such relationships affect health and disease.

Keywords:  Alzheimer’s disease; Gut dysbiosis; Gut-mitochondria axis; IBD; IgA nephropathy; ROS

DOI:  https://doi.org/10.1007/s11010-025-05397-7
J Transl Med. 2025 Oct 02. 23(1): 1044

FGF21 maintains redox homeostasis and promotes neuronal survival after traumatic brain injury by targeting SLC25A39-mediated mitochondrial GSH transport.

Lekai Wang, Weiwei Li, Xun Wu, Qing Ouyang, Bing Sun, Jianing Luo, Heng Guo, Tao Yang, Yuan Ma.

   BACKGROUND: Traumatic brain injury (TBI) represents a critical form of acute brain injury, characterized by considerable mortality and morbidity. Recently, fibroblast growth factor 21 (FGF21), a multifaceted hormone predominantly synthesized in liver, has emerged as a promising neuroprotective agent. In the study, we aim to investigate whether FGF21 exerts protective effects against TBI and to further elucidate its underlying molecular mechanisms.
METHODS: To elucidate the role of FGF21 in regulating SLC25A39-dependent mitochondrial GSH transport and providing protection against TBI-induced neurological deficits, a series of cellular and molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, transmission electron microscope, and behavioral assays, were employed.
RESULTS: FGF21 knockout exacerbates neural apoptosis and brain edema, increases lesion volume, and worsens neurological deficits following TBI. Remarkably, these pathological alterations were substantially mitigated with subsequent administration of recombinant FGF21. Importantly, FGF21 was found to prevent mitochondrial damage and sustain redox homeostasis post-TBI. Mechanistically, we observed that FGF21 enhances the mitochondrial uptake of glutathione (GSH), an essential redox metabolite, by targeting SLC25A39, a recently identified mitochondrial GSH transporter. FGF21 does not influence the transcriptional production of SLC25A39 but enhances its protein expression by inhibiting degradation via the mitochondrial protease AFG3L2. Furthermore, in neuron-specific Slc25a39 knockout mice, FGF21 was unable to exert its neuroprotective effects.
CONCLUSION: Our findings provide preliminary evidence that FGF21 confers protective effects against mitochondrial oxidative stress-related damage following TBI. Additionally, we elucidated a novel role for SLC25A39-dependent mitochondrial GSH transport in both the pathological processes subsequent to TBI and the physiological functions of FGF21.

Keywords:  Fibroblast growth factor 21; Glutathione; Mitochondria; Oxidative stress; SLC25A39; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12967-025-06969-3
Curr Issues Mol Biol. 2025 Sep 12. pii: 750. [Epub ahead of print]47(9):

Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights.

Guida Cai, Xi Zhang, Jiexi Jiao, Weijie Du, Meiling Yan.

  Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and chronic hyperglycemia, markedly increases the incidence and mortality of cardiovascular disease (CVD). Emerging preclinical evidence identifies the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway as a critical mediator of diabetic cardiovascular inflammation. Metabolic stressors in T2DM-hyperglycemia, lipotoxicity, and mitochondrial dysfunction-induce leakage of mitochondrial and microbial double-stranded DNA into the cytosol, where it engages cGAS and activates STING. Subsequent TBK1/IRF3 and NF-κB signaling drives low-grade inflammation across cardiomyocytes, endothelial cells, macrophages, and fibroblasts. Genetic deletion of cGAS or STING in high-fat-diet-fed diabetic mice reduces NLRP3 inflammasome-mediated pyroptosis, limits atherosclerotic lesion formation, and preserves cardiac contractile performance. Pharmacological inhibitors, including RU.521 (cGAS antagonist), C-176/H-151 (STING palmitoylation blockers), and the TBK1 inhibitor amlexanox, effectively lower pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and improve left ventricular ejection fraction in diabetic cardiomyopathy and ischemia-reperfusion injury models. Novel PROTAC degraders targeting cGAS/STING and natural products such as Astragaloside IV and Tanshinone IIA further support the pathway's druggability. Collectively, these findings position the cGAS-STING axis as a central molecular nexus linking metabolic derangement to cardiovascular pathology in T2DM and underscore its inhibition or targeted degradation as a promising dual cardiometabolic therapeutic strategy.

Keywords:  cGAS-STING signaling pathway; diabetic cardiovascular complications; immunological mediators; inflammatory responses; type 2 diabetes mellitus (T2DM)

DOI:  https://doi.org/10.3390/cimb47090750
Sci Rep. 2025 Oct 02. 15(1): 34356

Systematic review and meta-analysis of antioxidants with or without exercise training improving muscle condition in older adults.

Yijie Wang, Ziping He, Chunye Long, Yue Li, Yuzhe Yuan, Tianlong Huang.

  Oxidative stress and physical inactivity are regarded as important mechanisms contributing to muscle loss. However, the efficacy of antioxidants and their potential synergy with exercise training remain controversial for older population. The study aimed to evaluate the effects of antioxidants, either combined with or without exercise, on improving muscle strength, mass, and physical performance in older adults. We conducted a comprehensive search of the PubMed, MEDLINE, and Embase databases to identify randomized controlled trials (RCTs) on muscle condition in subjects aged 55 years or older. The search period covered from the inception of each database until June 10, 2024. A total of 39 RCTs involving 1714 participants were included. The meta-analysis presented that antioxidants alone could enhance muscle strength in 1 repetition maximum (RM) in leg press and physical function in the older population. Exercise alone could increase the walking distance of 6 min walk more than antioxidants alone. The combination of antioxidants and exercise further improved 1RM in leg press, usual walking speed and walking distance of 6 min walk compared to antioxidants alone. Additionally, this combination enhanced handgrip strength, 1RM in leg press and walking distance of 6 min walk more than exercise alone. This meta-analysis demonstrated that antioxidants alone had positive effects on muscle condition in older individuals. However, the combination of antioxidants and exercise was more effective than either intervention alone in improving muscle strength and physical function among the older adults.

Keywords:  Antioxidants; Exercise; Geriatrics; Muscle atrophy; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-16917-2
Mech Ageing Dev. 2025 Sep 26. pii: S0047-6374(25)00093-4. [Epub ahead of print]228 112117

The stress-responsive cytokine GDF-15 and sarcopenia: A systematic review and meta-analysis on aging muscle decline.

Mario Virgilio Papa, Chiara Ceolin, Francesco Boschele, Raffaele Pagliuca, Giuseppe Sergi, Marina De Rui.

   BACKGROUND: Given the increasing interest for Growth Differentiation Factor-15 (GDF-15) in muscle decline, this study aims to evaluate the association between circulating levels of GDF-15 and muscle mass and sarcopenia through a systematic review and meta-analysis.
METHODS: The research, in accordance with PRISMA and MOOSE guidelines, involved PubMed, Embase, and Cochrane Libraries. Two meta-analyses were performed: (1) comparison of GDF-15 levels in sarcopenic vs non-sarcopenic individuals; (2) correlation between GDF-15 and muscle mass.
RESULTS: A total of 7 studies met the inclusion criteria (total n = 2344) enrolling both adults aged ≥ 60 years (6/7 studies) and a younger cohort (42 years [IQR 31.8-51]). The first meta-analysis, based on 4 studies (n = 1393), showed significantly higher levels of GDF-15 in sarcopenic individuals (r = 0.482). The second meta-analysis, involving 4 studies (n = 1400), found a significant inverse correlation between GDF-15 and muscle mass (r = -0.221).
CONCLUSIONS: Sarcopenic individuals had higher circulating GDF-15. Together with the inverse correlation between GDF-15 and muscle mass observed, these findings show a small-to-moderate association between elevated GDF-15 and sarcopenic phenotypes in older adults. However, the limited number of studies and high heterogeneity for the sarcopenia comparison warrant cautious interpretation and underscore the need for larger, longitudinal investigations.

Keywords:  Aging; Biomarkers of aging; Cellular senescence; GDF-15; Mitochondrial stress; Muscle atrophy; Sarcopenia; Stress-responsive cytokine

DOI:  https://doi.org/10.1016/j.mad.2025.112117