bims-mistre 2025-05-18 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–05–18
eleven papers selected by
Ellen Siobhan Mitchell, MitoQ

Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.
Peumus boldus Extract Inhibits Lipid Accumulation in 3T3-L1 Adipocytes.
Mitochondrial unfolded protein response (UPRmt) as novel therapeutic targets for neurological disorders.
Rhythmic Insulin Induced by Eating During the Active Phase Promotes Skeletal Muscle Growth via Synchronizing Mitochondrial Energy Supply Rhythm and Cell Cycle.
Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
Mitochondrial transfer in endothelial cells and vascular health.
Neuroprotective potential of epigallocatechin gallate in Neurodegenerative Diseases: Insights into molecular mechanisms and clinical Relevance.
Targeting farnesoid X receptor as aging intervention therapy.
JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction.
Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies.
Therapeutic Aspects of Melatonin-sirtuin Crosstalk: An Updated Review of Current Data Based on Cellular Mechanisms.

J Cell Mol Med. 2025 May;29(9): e70588

Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.

Andrey Y Vinokurov, Pavel A Bazhenov, Marina Y Pogonyalova, Evgenia S Seryogina, Ekaterina A Vetrova, Larisa Andreeva, Andrey Y Abramov, Plamena R Angelova.

  Skeletal muscles constantly consume energy, and this consumption level increases correspondingly to the levels of physical activity. Mitochondrial energy metabolism requires constant supplementation with oxygen and substrates for ATP production. Limitation of the mitochondrial substrate supply leads to energy deprivation, which may be followed by sarcopenia and weight loss. Activation of mitochondrial energy metabolism can also stimulate the production of reactive oxygen species and oxidative stress. Here, we studied the effect of various mitochondrial substrates on the energy metabolism of primary skeletal myotubes and how it affects redox balance. We found that as individual components-glutamate, succinate, nicotinamide (NAM) as well as in combination-dicholine succinate (DISU) plus NAM, they increase mitochondrial membrane potential, alter NADH and FAD redox indices, which leads to an increased energy capacity of the skeletal myotubes. Changes in mitochondrial metabolism increased ROS production in mitochondria and cytosol but induced only a minor decrease in the level of the endogenous antioxidant reduced glutathione. Supplementation of young and aged rats with DISU + NAM through the drinking water for 7 days significantly increased myotube diameter in both age groups. Thus, provision of the myotubes with mitochondrial metabolism substrates activates energy metabolism and increases energy capacity but has no effect on oxidative stress. Moreover, it increases myotubes' diameters in young and aged rodent sarcopenia models in vivo.

Keywords:  energy metabolism; glutathione; mitochondria; myotubes; reactive oxygen species; sarcopenia

DOI:  https://doi.org/10.1111/jcmm.70588
Int J Mol Sci. 2025 May 02. pii: 4326. [Epub ahead of print]26(9):

Peumus boldus Extract Inhibits Lipid Accumulation in 3T3-L1 Adipocytes.

Laura Montaldo, Llerson Bendezu Meza, Mauricio De Marzi, Liliana Noemi Guerra.

  Obesity is a metabolic condition of epidemic scale. Previously, we showed that antioxidant extracts from Ribes nigrum had antioxidant and anti-adipogenic effects in mature adipocytes (AD). Here, we evaluated an aqueous extract from Peumus boldus (Boldo) in AD and studied its effect on reactive oxygen species (ROS) and lipid production. We analyzed the antioxidant activity (AA) of the Boldo extract using the DPPH technique and polyphenol (Pph) content via Folin's reagent. In AD, we evaluated ROS production, catalase (CAT) activity, intracellular triglyceride (Tg) and cholesterol (Chol) contents, nitric oxide (NO) production via Griess reagent, and the levels of glycerol (Gly) and TNF-α released in the culture medium. We showed that the Boldo extract has high AA. In vitro, Boldo treatment decreased ROS intracellular production and CAT activity. In addition, the Boldo extract was effective in reducing Tg and Chol levels and NO production. We did not identify significant differences in Gly released or TNF-α secreted. We suggest that the Boldo extract has antioxidant and anti-adipogenic effects, but we did not observe lipolytic effects. Boldo did not modify inflammatory markers.

Keywords:  adipocytes; antioxidants; oxidative stress; polyphenols

DOI:  https://doi.org/10.3390/ijms26094326
J Cereb Blood Flow Metab. 2025 May 15. 271678X251341293

Mitochondrial unfolded protein response (UPRmt) as novel therapeutic targets for neurological disorders.

Xi Chen, Hong An, Jiachen He, Jiaqi Guo, Shuaili Xu, Chuanjie Wu, Di Wu, Xunming Ji.

  Neurological disorders, including brain cancer, neurodegenerative diseases and ischemic/reperfusion injury, pose a significant threat to global human health. Due to the high metabolic demands of nerve cells, mitochondrial dysfunction is a critical feature of these disorders. The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response, which is critical for maintaining mitochondrial and energetic homeostasis under stress. Previous studies have found that UPRmt participates in diverse physiological processes especially metabolism and immunity. Currently, increasing evidence suggest that targeted regulation of UPRmt can also effectively delay the progression of neurological diseases and improve patients' prognosis. This review provides a comprehensive overview of UPRmt in the context of neurological diseases, with a particular emphasis on its regulatory functions. Additionally, we summarize the mechanistic insights into UPRmt in neurological disorders as investigated in preclinical studies, as well as its potential as a therapeutic target in the clinical management of neurological tumors. By highlighting the importance of UPRmt in the complex processes underlying neurological disorders, this review aims to bridge current knowledge gaps and inspire novel therapeutic strategies for these conditions.

Keywords:  Mitochondria; aging; neurological disorders; therapy; unfolded protein response

DOI:  https://doi.org/10.1177/0271678X251341293
FASEB J. 2025 May 31. 39(10): e70619

Rhythmic Insulin Induced by Eating During the Active Phase Promotes Skeletal Muscle Growth via Synchronizing Mitochondrial Energy Supply Rhythm and Cell Cycle.

Chunhua Shan, Lei Zhang, Xiaohan Ma, Wenlong Lv, Quangang Wang, Kehao Zhang, Mengqi Zhu, Jianxiang Cheng, Yao Guo, Zhongying Liu, Shan Ling, Zhonghong Wu.

  Food intake during the inactive period disrupts the metabolic rhythm of skeletal muscle. Energy metabolism is closely related to muscle growth. However, the impact of eating time on skeletal muscle growth remains unclear. In this study, nocturnal rabbits were subjected to day-restricted feeding (DRF) and night-restricted feeding (NRF), and it was found that DRF disrupted insulin rhythm, whereas NRF enhanced insulin rhythm and promoted skeletal muscle growth. The pathway analyzed by RNA-seq found that circadian rhythm and pancreatic secretion pathways were enriched in Tibialis anterior muscle. Mechanistically, we found that rhythmic insulin couples mitochondrial oxidative phosphorylation rhythm with mitochondrial fission-fusion rhythm by altering BMAL1 phase, which synchronized mitochondrial ATP production rhythm with the G1/S phase progression of the cell cycle and thus promoted myoblast proliferation. Our findings suggest that food intake during the active phase enhances insulin-mediated mitochondrial energy supply rhythm, thereby promoting skeletal muscle growth. This study provides a new perspective for guiding a healthy diet for growth in children and farm animals.

Keywords:  cell cycle; circadian rhythm; eating time; insulin; mitochondria; muscle growth

DOI:  https://doi.org/10.1096/fj.202500529R
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122

Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.

Weiwei Fan, Tae Gyu Oh, Hui J Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan L Truitt, Christopher Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle

DOI:  https://doi.org/10.1073/pnas.2426179122
Trends Cell Biol. 2025 May 13. pii: S0962-8924(25)00105-9. [Epub ahead of print]

Mitochondrial transfer in endothelial cells and vascular health.

Gwang-Bum Im, Juan M Melero-Martin.

  Mitochondria play a vital role in cellular energy metabolism and vascular health, with their function directly influencing endothelial cell (EC) bioenergetics and integrity. Mitochondrial transfer has emerged as a key mechanism of intercellular communication, impacting angiogenesis, tissue repair, and cellular homeostasis. This review highlights recent findings on mitochondrial transfer, including natural mechanisms - such as tunneling nanotubes (TNTs) and extracellular vesicles (EVs) - and artificial approaches like mitochondrial transplantation. These processes enhance EC function and support vascularization under pathological conditions, including ischemia. While early clinical trials demonstrate therapeutic potential, challenges such as mitochondrial instability and scaling host-derived mitochondria persist. Continued research is essential to optimize mitochondrial transfer and advance its application as a therapeutic strategy for restoring vascular health.

Keywords:  angiogenesis; endothelial cells; mitochondrial transfer; mitochondrial transplantation; vascular regeneration

DOI:  https://doi.org/10.1016/j.tcb.2025.04.004
Brain Res. 2025 May 09. pii: S0006-8993(25)00252-5. [Epub ahead of print]1860 149693

Neuroprotective potential of epigallocatechin gallate in Neurodegenerative Diseases: Insights into molecular mechanisms and clinical Relevance.

Md Al Amin, Mehrukh Zehravi, Sherouk Hussein Sweilam, Mst Maharunnasa Shatu, Trupti Pratik Durgawale, Mohammad Shamim Qureshi, Sumit Durgapal, M Akiful Haque, Rajeshwar Vodeti, Uttam Prasad Panigrahy, Irfan Ahmad, Sharuk L Khan, Talha Bin Emran.

  Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis pose significant challenges due to their complex pathophysiology and lack of effective treatments. Green tea, rich in the epigallocatechin gallate (EGCG) polyphenolic component, has demonstrated potential as a neuroprotective agent with numerous medicinal applications. EGCG effectively reduces tau and Aβ aggregation in ND models, promotes autophagy, and targets key signaling pathways like Nrf2-ARE, NF-κB, and MAPK. This review explores the molecular processes that underlie EGCG's neuroprotective properties, including its ability to regulate mitochondrial dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Clinical research indicates that EGCG may enhance cognitive and motor abilities, potentially inhibiting disease progression despite absorption and dose optimization limitations. The substance has been proven to slow the amyloidogenic process, prevent protein aggregation, decrease amyloid cytotoxicity, inhibit fibrillogenesis, and restructure fibrils for synergistic therapeutic effects. The review highlights the potential of EGCG as a natural, multi-targeted strategy for NDs but emphasizes the need for further clinical trials to enhance its therapeutic efficacy.

Keywords:  Clinical studies; Epigallocatechin Gallate; Neurodegenerative diseases; Neuroinflammation; Neuroprotection; Oxidative stress

DOI:  https://doi.org/10.1016/j.brainres.2025.149693
Acta Pharm Sin B. 2025 Mar;15(3): 1359-1382

Targeting farnesoid X receptor as aging intervention therapy.

Lijun Zhang, Jing Yu, Xiaoyan Gao, Yingxuan Yan, Xinyi Wang, Hang Shi, Minglv Fang, Ying Liu, Young-Bum Kim, Huanhu Zhu, Xiaojun Wu, Cheng Huang, Shengjie Fan.

  Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr -/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.

Keywords:  Aging; Detoxification; Farnesoid X receptor; Healthspan; Lifespan; Longevity; Obeticholic acid; Pregnane X receptor

DOI:  https://doi.org/10.1016/j.apsb.2025.01.006
Mol Med. 2025 May 13. 31(1): 184

JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction.

Dewei Peng, Xiaoli He, Bowen Ren, Qian Wang, Lulu Peng, Yue Jiang, Shengqi Huo, Lintong Men, Wei Shi, Pengcheng Luo, Mengyin Zhu, Cuntai Zhang, Jiagao Lv, Li Lin, Sheng Li.

   BACKGROUND: High uric acid levels play a critical role in cardiovascular disease pathophysiology, being closely linked to their occurrence, progression, and prognosis. To enhance prevention and treatment of hyperuricemia-related cardiovascular diseases, understanding underlying mechanisms and identifying novel therapeutic targets are essential.
METHODS: A hyperuricemic mouse model was established, and transcriptomic analysis of myocardial tissue was conducted using RNA sequencing. The role of HMGCS2 in hyperuricemia-induced cardiomyocytes was investigated through HMGCS2 knockout. The transcriptional regulation of HMGCS2 by STAT3 was explored via STAT3 knockdown, overexpression, and dual-luciferase reporter assays. To further elucidate the role of the JAK2/STAT3/hmgcs2 signaling pathway in hyperuricemia-induced cardiomyocytes, we overexpressed HMGCS2 while intervening in the JAK2/STAT3 pathway in vitro. The therapeutic potential of targeting the JAK2/STAT3/HMGCS2 pathway was evaluated in hyperuricemic mice using STAT3 and JAK inhibitors to assess effects on cardiac dysfunction.
RESULTS: RNA sequencing showed significant upregulation of HMGCS2 mRNA in hyperuricemic mouse cardiac tissue. Increased HMGCS2 protein levels were observed in cardiac tissue and AC16 cardiomyocytes. HMGCS2 knockdown alleviated uric acid-induced mitochondrial dysfunction, oxidative stress, and abnormal energy metabolism in AC16 cardiomyocytes. And high uric acid levels activate the IL-6/JAK2/STAT3 signaling pathway in AC16 cardiomyocytes, which regulates HMGCS2 expression. By modulating JAK2 and STAT3 expression and subsequently overexpressing HMGCS2, we identified the involvement of the JAK2/STAT3/HMGCS2 pathway in uric acid-induced mitochondrial dysfunction, oxidative stress, and energy metabolism abnormalities in AC16 cardiomyocytes. In vitro experiments demonstrated that intervention with the ruxolitinib and S3I-201 could ameliorate mitochondrial dysfunction, oxidative stress, and ATP levels in the heart tissue of hyperuricemic mice. Moreover, these treatments also reversed cardiac function abnormalities.
CONCLUSIONS: The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage.

Keywords:  Cardiac dysfunction; HMGCS2; Hyperuricemia; JAK2; Mitochondrial function; STAT3

DOI:  https://doi.org/10.1186/s10020-025-01246-x
Diabetes Metab J. 2025 May;49(3): 333-347

Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies.

Joon Seok Park, Kyu Sik Kim, Hyung Jin Choi.

  Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.

Keywords:  Central nervous system; Diabetes mellitus, type 2; Glucagon-like peptide 1; Glucagon-like peptide-1 receptor; Glucagon-like peptide-1 receptor agonists; Hypothalamus; Incretins

DOI:  https://doi.org/10.4093/dmj.2025.0106
Curr Drug Targets. 2025 May 14.

Therapeutic Aspects of Melatonin-sirtuin Crosstalk: An Updated Review of Current Data Based on Cellular Mechanisms.

Azam Hosseinzadeh, Rarnoosh Seirafianpour, Mohammad Sheibani, Maryam Taheri, Ali Jamshidi Naeini, Russel J Reiter, Saeed Mehrzadi.

  Melatonin, a master regulator of circadian rhythms and diverse physiological processes, exhibits complex interactions with various molecules. Sirtuins, a family of histone deacetylases, are key players in aging, stress responses, and metabolism and represent a critical target for melatonin. This review explores the multifaceted functions of melatonin and sirtuins, delving into the molecular mechanisms of their interaction. We further examine the impact of this synergy on various pathologies across different organs. Studies suggest that melatonin modulates SIRT1 and SIRT3 signaling pathways, offering protection in neurodegenerative, cardiovascular, skeletal, and pulmonary diseases, as well as renal and hepatic dysfunction. Additionally, melatonin-sirtuin interactions have been implicated in mitigating cancer development and promoting health in the female and male reproductive systems. Notably, the majority of studies across these systems demonstrate melatonin's ability to regulate SIRT1 and SIRT3 signaling, thereby alleviating associated pathologies. In conclusion, the intricate interplay between melatonin and, particularly, SIRT1 and SIRT3 emerges as a crucial modulator of diverse signaling pathways, with promising therapeutic implications for a wide range of diseases.

Keywords:  Melatonin; SIRT1; SIRT3; aging; cancer; circadian rhythm; neurodegeneration; signaling pathways.; sirtuins family

DOI:  https://doi.org/10.2174/0113894501360934250512052503