bims-mistre 2025-03-30 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–03–30
thirteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics.
Reductive Stress and Mitochondrial Dysfunction: The Hidden Link in Chronic Disease.
Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
Reactive Oxygen Species (ROS) in Metabolic Disease-Don't Shoot the Metabolic Messenger.
Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.
Molecular mechanism of melatonin-mediated mitophagy regulating proline production to ameliorate skin aging.
Mitochondria targeted nanoparticles for the treatment of mitochondrial dysfunction-associated brain disorders.
Function of intramitochondrial melatonin and its association with Warburg metabolism.
The fate of mitochondrial respiratory complexes in aging.
Isoquercitrin Attenuates Oxidative Liver Damage Through AMPK-YAP Signaling: An Integrative In Silico, In Vitro, and In Vivo Study.
The contribution of dietary total antioxidant capacity to type 2 diabetes risk and levels of glycemic biomarkers: a systematic review.
Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 Mice.
IL-6 Induces Mitochondrial ROS Production and Blunts NO Bioavailability in Human Aortic Endothelial Cells.

Ageing Res Rev. 2025 Mar 22. pii: S1568-1637(25)00078-9. [Epub ahead of print]108 102732

Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics.

Shadt Skawratananond, Daniel X Xiong, Charlie Zhang, Sahil Tonk, Aljon Pinili, Brad Delacruz, Patrick Pham, Shane C Smith, Rahul Navab, P Hemachandra Reddy.

  Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.

Keywords:  Aging; Alzheimer’s disease; Diabetes; Metabolic disorders; Mitochondrial dysfunction; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2025.102732
Free Radic Biol Med. 2025 Mar 22. pii: S0891-5849(25)00179-0. [Epub ahead of print]

Reductive Stress and Mitochondrial Dysfunction: The Hidden Link in Chronic Disease.

Joseph Mercola.

Conventional theories of oxidative stress have long focused on the deleterious consequences of excessive reactive oxygen species (ROS) formation. However, growing evidence reveals that an overload of reducing equivalents-termed reductive stress-may be equally pivotal in driving mitochondrial dysfunction and chronic disease. In this paradigm, abnormally high concentrations of NADH and NADPH create an electron "traffic jam" in the mitochondrial electron transport chain (ETC), leading to partial inhibition or reverse electron flow at upstream complexes. Paradoxically, this hyper-reduced environment promotes ROS generation by increasing electron leakage to molecular oxygen, thereby intensifying oxidative damage to lipids, proteins, and mitochondrial DNA. This review explores the intertwined nature of reductive and oxidative stress, showing how a surplus of reducing equivalents can potentiate metabolic derangements in conditions such as type 2 diabetes, nonalcoholic fatty liver disease, and neurodegenerative disorders. We discuss common drivers of reductive overload, including chronic hyperglycemia, high-fat diets, and specific dietary patterns-particularly those enriched in polyunsaturated omega-6 fatty acids-that inundate mitochondria with electron donors. We also highlight emerging evidence that targeted assessment of redox biomarkers (e.g., lactate:pyruvate, β-hydroxybutyrate:acetoacetate ratios) can provide clinically relevant indicators of reductive stress. Finally, we examine how novel therapeutic strategies can address the underlying reductive imbalance, from rational nutrient modulation to pharmacologic interventions that restore NAD+ levels or optimize ETC flux. Recognizing reductive stress as a critical inflection point in mitochondrial pathophysiology underscores the need for a refined redox framework, one that moves beyond conventional oxidative paradigms to embrace the full spectrum of redox dysregulation in chronic degenerative disease.

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.03.029
Diabetes Res Clin Pract. 2025 Mar 23. pii: S0168-8227(25)00143-3. [Epub ahead of print] 112129

Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.

Amna Aqeel, Areeba Akram, Minahil Ali, Maryam Iqbal, Mehral Aslam, Rukhma Sattar, Fatima Iftikhar Shah.

  Mitochondria, also known as the powerhouse of cells, have an important role in cellular metabolism and energy production. However, during Mitochondrial Dysfunction (MD), it is known to generate reactive oxidative species and induce cellular apoptosis. A number of research findings have linked MD to various diseases, highlighting its critical role in maintaining health and contributing to disease development. In this regard, recent research has revealed that disruptions in lipid metabolism, especially in fatty acid oxidation, are significant contributors to MD. However, the precise mechanisms by which these defects lead to disease remain poorly understood. This review explores how disruptions in lipid metabolism are responsible for triggering oxidative stress, inflammation, and cellular damage, leading to impaired mitochondrial function. By examining specific fatty acid oxidation disorders, such as carnitine palmitoyltransferase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency, this review aims to uncover the underlying molecular pathways connecting lipid metabolism to mitochondrial dysfunction. Furthermore, MD is a common underlying mechanism in a wide array of diseases, including neurodegenerative disorders, and metabolic syndromes. Understanding the mechanisms behind mitochondrial malfunction may aid in the development of tailored therapies to restore mitochondrial health and treat intricate health conditions.

Keywords:  Fatty acid oxidation disorders (FAODs); Lipid metabolism; Mitochondrial dysfunction; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.diabres.2025.112129
Int J Mol Sci. 2025 Mar 14. pii: 2622. [Epub ahead of print]26(6):

Reactive Oxygen Species (ROS) in Metabolic Disease-Don't Shoot the Metabolic Messenger.

Ross T Lindsay, Christopher J Rhodes.

  Reactive oxygen species (ROS) are widely considered key to pathogenesis in chronic metabolic disease. Consequently, much attention is rightly focused on minimising oxidative damage. However, for ROS production to be most effectively modulated, it is crucial to first appreciate that ROS do not solely function as pathological mediators. There are >90 gene products specifically evolved to generate, handle, and tightly buffer the cellular concentration of ROS. Therefore, it is likely that ROS plays a role as integral homeostatic signalling components and only become toxic in extremis. This review explores these commonly overlooked normal physiological functions, including how ROS are generated in response to environmental or hormonal stimuli, the mechanisms by which the signals are propagated and regulated, and how the cell effectively brings the signal to an end after an appropriate duration. In the course of this, several specific and better-characterised signalling mechanisms that rely upon ROS are explored, and the threshold at which ROS cross from beneficial signalling molecules to pathology mediators is discussed.

Keywords:  cellular second messenger; endoplasmic reticulum (ER); metabolic disease; mitochondria; oxidation; peroxisome; reactive oxygen species (ROS) signalling

DOI:  https://doi.org/10.3390/ijms26062622
Adv Biol (Weinh). 2025 Mar 24. e2400597

Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.

Amrita Nepalia, Deepak Kumar Saini.

  Mitochondrial dysfunction is an irrefutable hallmark of cellular senescence and aging. The dysfunction is marked by increased mitochondrial volume and reduced function, typified by low Adenosine Triphosphate (ATP) production and higher Reactive Oxygen Species (ROS) generation. Over the years, this dysfunction has been linked to Electron Transport Chain (ETC) malfunction and low NAD levels, augmented by poor mitophagy. However, the genetic regulation of mitochondrial dysfunction is still not clear. Here, using several senescence models, the first report on the role of the downregulation of a mitochondrial protein, Translocase of Inner Mitochondrial Membrane 50 (TIMM50), in senescence is presented. The downregulation of TIMM50 is also sufficient for triggering senescence through impaired mitochondrial function, characterized using a variety of mitochondrial function assessment assays. Reduced levels of TIMM50 initiated all the hallmarks of senescence, and overexpression significantly slowed senescence onset in response to an external trigger. The pathway analysis revealed that TIMM50 loss is mediated by the sirtuin1-dependent downregulation of CCAAT enhancer binding protein alpha (CEBPα), a transcription activator for TIMM50 expression. To establish the translational value of the observation, screening several potential anti-aging compounds revealed TIMM50 stabilizing and senescence-delaying effects only for verapamil and mitochondrial ROS quencher, Mito (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), both known anti-aging entities. Overall, TIMM50 is identified as the key mitochondrial protein whose downregulation is a critical step in initiating cellular senescence.

Keywords:  TIMM50; aging; cellular senescence; mitochondria; sirtuin

DOI:  https://doi.org/10.1002/adbi.202400597
Exp Gerontol. 2025 Mar 25. pii: S0531-5565(25)00067-1. [Epub ahead of print]204 112738

Molecular mechanism of melatonin-mediated mitophagy regulating proline production to ameliorate skin aging.

Tao Quan, Ran Li, Ting Gao.

  Collagen loss is one of the major contributor to signs of skin aging such as dryness, roughness, and wrinkle formation, which is closely linked to a decline in the amount of proline produced in mitochondria. Melatonin has been shown to improve several clinical signs of skin aging, while the mechanism is unclear. In our study, we found that mitophagy, proline synthesis key enzyme NADK2 and proline and collagen levels were significantly reduced, while oxidative stress levels increased in aging skin, and melatonin supplementation could effectively up-regulate mitophagy level and restore proline synthesis and further improved skin aging. However, proline supplementation could also exert an anti-aging effect, while it had no effect on the mitochondrial dysfunction. Moreover, our study indicated that melatonin enters the cell by binding to the MT1 receptor and then enters the mitochondria via the PEPT1 transporter to exert its mitochondrial protective effects. This study helps to elucidate the mechanism of mitochondrial dysfunction-induced skin aging, and provides new theoretical guidance for revealing the mechanism of skin aging and rationally utilizing endocrine hormones to improve skin aging, which has a broad application prospect.

Keywords:  Collagen; Melatonin; Mitophagy; Proline; Skin aging

DOI:  https://doi.org/10.1016/j.exger.2025.112738
Front Bioeng Biotechnol. 2025 ;13 1563701

Mitochondria targeted nanoparticles for the treatment of mitochondrial dysfunction-associated brain disorders.

Amy Claire Buck, Gerald J Maarman, Admire Dube, Soraya Bardien.

  Mitochondria play a significant role in several cellular activities and their function in health and disease has become an important area of research. Since the brain is a high-energy-demanding organ, it is particularly vulnerable to mitochondrial dysfunction. This has been implicated in several brain disorders including neurodegenerative, psychiatric and neurological disorders, e.g., Parkinson's disease and schizophrenia. Significant efforts are underway to develop mitochondria-targeting pharmaceutical interventions. However, the complex mitochondrial membrane network restricts the entry of therapeutic compounds into the mitochondrial matrix. Nanoparticles (NPs) present a novel solution to this limitation, while also increasing the stability of the therapeutic moieties and improving their bioavailability. This article provides a detailed overview of studies that have investigated the treatment of mitochondrial dysfunction in brain disorders using either targeted or non-targeted NPs as drug delivery systems. All the NPs showed improved mitochondrial functioning including a reduction in reactive oxygen species (ROS) production, an improvement in overall mitochondrial respiration and a reversal of toxin-induced mitochondrial damage. However, the mitochondrial-targeted NPs showed an advantage over the non-targeted NPs as they were able to improve or rescue mitochondrial dynamics and biogenesis, and they required a lower concentration of the in vivo therapeutic dosage of the drug load to show an effect. Consequently, mitochondria-targeted NPs are a promising therapeutic approach. Future studies should exploit advances in nanotechnology, neuroscience and chemistry to design NPs that can cross the blood-brain barrier and selectively target dysfunctional mitochondria, to improve treatment outcomes.

Keywords:  brain disorders; mitochondria-targeted nanoparticles; mitochondrial dysfunction; nanomedicine; therapy

DOI:  https://doi.org/10.3389/fbioe.2025.1563701
Cell Signal. 2025 Mar 21. pii: S0898-6568(25)00167-6. [Epub ahead of print]131 111754

Function of intramitochondrial melatonin and its association with Warburg metabolism.

Russel J Reiter, Ramaswamy Sharma, Yidong Bai, Luiz Gustavo de Almeida Chuffa, Doris Loh, Lihong Fan, Daniel P Cardinali.

  Warburg metabolism (aerobic glycolysis) is accompanied by high mitochondrial reactive oxygen species (ROS) generation from the electron transport chain; this is a "Hallmark of Cancer". The elevated ROS sustain the growth and proliferation of the cancer cells. Melatonin is a potent and functionally diverse free radical scavenger and antioxidant that is synthesized in the mitochondria of non-pathological cells and normally aids in keeping mitochondrial ROS levels low and in maintaining redox homeostasis. Because the glucose metabolite, pyruvate, does not enter mitochondria of Warburg metabolizing cells due to the inhibition of pyruvate dehydrogenase complex (PDH), acetyl coenzyme A production is diminished. Acetyl coenzyme A is a necessary co-substrate with serotonin for melatonin synthesis; thus, intramitochondrial melatonin levels become reduced in cancer cells. The hypothesis is that the depressed melatonin levels initiate aerobic glycolysis and allow the exaggerated ROS concentrations to go uncontested; the authors speculate that the elevated mtROS upregulates hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase (PDK) axis which inhibits PDH, thereby supporting cancer cell proliferation and stimulating cancer biomass. Exposing Warburg metabolizing cancer cells to melatonin elevates intramitochondrial melatonin, thereby reducing mtROS and concurrently interrupting aerobic glycolysis and inhibiting tumor cell proliferation. Mechanistically, higher mitochondrial melatonin levels by supplementation directly upregulates the sirtuin 3 (SIRT3)/FOXO/PDH axis, allowing pyruvate entry into mitochondria and enhancing intrinsic mitochondrial melatonin production as in non-pathological cells. Additionally, melatonin inhibits HIF1α, thereby decreasing PDK activity and disinhibiting PDH, so pyruvate enters mitochondria and is metabolized to acetyl coenzyme A, resulting in reversal of Warburg metabolism.

Keywords:  Acetyl coenzyme A; Antioxidant; Hypoxia inducible factor; Pyruvate dehydrogenase; Pyruvate metabolism; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cellsig.2025.111754
Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]

The fate of mitochondrial respiratory complexes in aging.

Hanna Salmonowicz, Karolina Szczepanowska.

  While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.

Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks

DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
Int J Mol Sci. 2025 Mar 18. pii: 2717. [Epub ahead of print]26(6):

Isoquercitrin Attenuates Oxidative Liver Damage Through AMPK-YAP Signaling: An Integrative In Silico, In Vitro, and In Vivo Study.

So-Hyun Kwon, Won-Yung Lee, Young Woo Kim, Kwang Suk Ko, Seon Been Bak, Sun-Dong Park.

  Isoquercitrin, a flavonoid glycoside found in various plants, has demonstrated antioxidant, anti-inflammatory, and anticancer properties. However, its hepatoprotective effects and underlying mechanisms against oxidative liver injury remain unclear. In this study, we evaluated the antioxidant and hepatoprotective effects of isoquercitrin using integrated in silico, in vitro, and in vivo approaches. HepG2 cells exposed to arachidonic acid (AA) and iron exhibited oxidative stress-induced apoptosis, which was significantly attenuated by isoquercitrin treatment, as evidenced by increased cell viability and reduced apoptosis-related protein alterations. Isoquercitrin decreased reactive oxygen species (ROS) generation and preserved mitochondrial function in a dose-dependent manner. Molecular docking and Western blot analyses revealed that isoquercitrin activates the LKB1/AMPK pathway, increasing phosphorylation of AMPK and its downstream target ACC, thereby modulating energy metabolism and reducing oxidative stress. This activation was LKB1 dependent, as confirmed in LKB1-deficient HeLa cells. Additionally, isoquercitrin modulated the YAP signaling pathway in hepatic cells. In vivo, isoquercitrin protected mice against carbon tetrachloride-induced liver injury, reducing serum ALT and AST levels and improving histopathological features. These findings suggest that isoquercitrin exerts hepatoprotective effects by activating the LKB1/AMPK pathway and modulating metabolic enzymes, highlighting its potential as a therapeutic agent against oxidative liver damage.

Keywords:  LKB1/AMPK pathway; antioxidant activity; hepatoprotective effects; isoquercitrin; oxidative liver damage

DOI:  https://doi.org/10.3390/ijms26062717
Osong Public Health Res Perspect. 2025 Mar 27.

The contribution of dietary total antioxidant capacity to type 2 diabetes risk and levels of glycemic biomarkers: a systematic review.

Sorayya Kheirouri, Hamed Alizadeh.

   Objectives: This study systematically reviewed and analyzed epidemiological evidence regarding the association between dietary total antioxidant capacity (DTAC) and both the risk of developing diabetes and glycemic biomarker levels.
Methods: We searched the PubMed, Scopus, ScienceDirect, and Google Scholar databases through July 2024 without imposing any date restrictions. Original studies that examined the relationship between DTAC and either the risk of developing diabetes or glycemic biomarker levels-specifically fasting blood glucose (FBG), hemoglobin A1C (HbA1C), insulin, and the homeostatic model assessment for insulin resistance (HOMA-IR)-were eligible for inclusion. After eliminating duplicates and irrelevant records, relevant studies were selected, and data were extracted through rigorous critical analysis.
Results: A total of 32 articles were included in the review. Of the 19 studies that evaluated diabetes risk, 15 reported a lower risk among subjects with higher DTAC values. All 4 studies examining prediabetes risk found lower risk in participants with high DTAC scores. Additionally, significant inverse relationships were observed between DTAC values and FBG (9/15 studies), HbA1C (1/6 studies), insulin (5/6 studies), and HOMA-IR (8/9 studies).
Conclusion: The majority of evidence indicates that high adherence to an antioxidant-rich diet may reduce diabetes risk and improve glycemic biomarkers, including FBG, insulin, and HOMA-IR.

Keywords:  Blood glucose; Diabetes mellitus; Dietary total antioxidant capacity; Glycated hemoglobin; Insulin; Insulin resistance

DOI:  https://doi.org/10.24171/j.phrp.2024.0337
Mol Neurobiol. 2025 Mar 25.

Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 Mice.

Juan Wang, Meiqing Liao, Zhen Tong, Shunling Yuan, Zelin Hu, Zeyu Chen, Fanqi Zeng, Ruihan Zou, Dandan Chen, Gan Chen, Zhiyuan Wang, Wenfeng Liu.

  Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.

Keywords:  Glial cell; High-fat diet; Leptin; Leptin resistance; Neuroinflammation; Treadmill running

DOI:  https://doi.org/10.1007/s12035-025-04853-1
Am J Physiol Regul Integr Comp Physiol. 2025 Mar 25.

IL-6 Induces Mitochondrial ROS Production and Blunts NO Bioavailability in Human Aortic Endothelial Cells.

Prema Velusamy, David J Buckley, Jody L Greaney, Adam J Case, Paul J Fadel, Daniel W Trott.

  Chronic inflammation is a major contributor to the development of endothelial dysfunction. Circulating concentrations of the proinflammatory cytokine interleukin-6 (IL- 6) have been shown to predict cardiovascular disease risk and are associated with the development of vascular dysfunction. However, the mechanisms that underlie inflammation induced endothelial dysfunction are not fully understood. Vascular endothelial dysfunction is characterized by blunted nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS), with mitochondrial ROS suggested to play a primary role. Therefore, we tested the hypothesis that IL-6 induces mitochondrial ROS production and blunts NO bioavailability in endothelial cells. To study the effect of IL-6, we treated the human aortic endothelial cells (HAECs) with IL-6, MitoTEMPOL (MT; a mitochondria targeted antioxidant), and/or a nitric oxide synthase (NOS) inhibitor (L- NAME) with and without ACh stimulation. Results are expressed as mean ± SD (n=4 43 replicates), one-way ANOVA and Bonferroni's post-hoc tests were performed. IL-6 44 treatment resulted in greater mitochondrial ROS (IL-6: 2.94 ± 0.93 a.u.) when compared 45 to the untreated cells (Control: 1 ± 0; p=0.0021) and also blunted NO bioavailability at 46 baseline (Control: 1 ± 0; IL-6: 0.57 ± 0.08 a.u. p=0.0008) and with acetylcholine 47 stimulation (Control Ach: 1.27 ± 0.09; IL-6 Ach: 0.60 ± 0.13 a.u. p<0.0001). Scavenging 48 mitochondrial ROS with MT restored NO bioavailability in the IL-6 treated cells (IL-6: 49 0.57 ± 0.08; IL-6 MT: 1.16 ± 0.20 a.u. p<0.0001). These findings indicate that IL-6 has a 50 direct effect on mitochondrial ROS in human aortic endothelial cells, which leads to 51 reduced nitric oxide bioavailability.

Keywords:  Endothelium; Inflammation; MitoTEMPOL; Vascular dysfunction

DOI:  https://doi.org/10.1152/ajpregu.00289.2024