bims-cesemi 2025-08-31 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–08–31
twenty-two papers selected by
Julio Cesar Cardenas, Universidad Mayor

Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.
KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.
Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction.
Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
Talazoparib and radiation enhance the senolytic efficacy of venetoclax in therapy-induced senescent triple-negative breast cancer cells.
Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.
Oxidative fragmentation of collagen in skin - relevance to skin aging and skin diseases.
Downregulation of microRNA-494 drives mitochondrial biogenesis and function in trained muscle.
Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.
Cancer as a failed response to renegade mitochondria.
Repeated heatwaves can age you as much as smoking or drinking.
Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle.
α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
NAD+ dyshomeostasis in RYR1-related myopathies.
Redox-Regulated Pathways in Glioblastoma Stem-like Cells: Mechanistic Insights and Therapeutic Implications.
Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.
Dual-key cooperatively activated DNA regulator for controlling mitochondria-lysosome interactions.
Aging-related, senescence-associated secretory phenotype and allogeneic hematopoietic cell transplantation outcomes in older patients.
MRPL12 K163 acetylation inhibits ccRCC via driving mitochondrial metabolic reprogramming.
TRAP1 promotes self-renewal and tumorigenicity of glioblastoma stem cells by inhibiting Notch1 ubiquitination.
α-Ketoglutarate Attenuates Oxidative Stress-Induced Neuronal Aging via Modulation of the mTOR Pathway.
Branched-Chain Amino Acids Combined with Exercise Improves Physical Function and Quality of Life in Older Adults: Results from a Pilot Randomized Controlled Trial.

Cell Prolif. 2025 Aug 24. e70120

Ageing-Dependent Thyroid Hormone Receptor α Reduction Activates IP3R1-Meditated Ca2+ Transfer in MAM and Exacerbates Skeletal Muscle Atrophy in Mice.

Runqing Shi, Yusheng Zhang, Gong Chen, Jiru Zhang, Jing Liu, Hao Zhu, Minne Sun, Yu Duan.

  Sarcopenia profoundly impacts the quality of life and longevity in elderly populations. Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TRα). Emerging evidence suggests that decreased TRα expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TRα deficiency in sarcopenia are not fully understood. This study suggests that TRα may regulate mitochondrial calcium (Ca2+) transport across membranes by targeting the inositol 1,4,5-trisphosphate receptor 1 (IP3R1), as evidenced by ChIP-seq and RNA-seq analyses. Experiments using naturally aged mice, skeletal muscle-specific TRα knockout (SKT) mice, and C2C12 myoblasts were conducted to investigate this process further. Findings include increased IP3R1, mitochondria-associated endoplasmic reticulum membranes (MAM), and mitochondrial Ca2+ in aged skeletal muscle. Additionally, SKT mice exhibited smaller muscle fibres, increased IP3R1 and MAM, and mitochondrial dysfunction. ChIP-qPCR and TRα manipulation in C2C12 cells showed that TRα negatively regulates IP3R1 transcription. Moreover, TRα knockdown cells exhibited increased Ca2+ transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2-aminoethoxydiphenyl borate. Reintroduction of TRα improved IP3R1-mediated mitochondrial Ca2+ overload in aged cells. Our findings uncover a novel mechanism by which TRα deficiency induces mitochondrial Ca2+ overload through IP3R1-mediated Ca2+ transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TRα/IP3R1 pathway in MAM Ca2+ transfer presents a potential therapeutic target for sarcopenia.

Keywords:  IP3R1; MAM; mitochondrial Ca2+ overload; sarcopenia; senescence; thyroid hormone receptor α

DOI:  https://doi.org/10.1111/cpr.70120
Aging Cell. 2025 Aug 24. e70194

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Boyi Zhang, Qilai Long, Shanshan Wu, Qixia Xu, Shuling Song, Liu Han, Min Qian, Xiaohui Ren, Hanxin Liu, Jing Jiang, Jianming Guo, Xiaoling Zhang, Xing Chang, Qiang Fu, Eric W-F Lam, Judith Campisi, James L Kirkland, Yu Sun.

  Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of patients with prostate cancer after chemotherapy. Global chromatin accessibility mapping via assay for transposase-accessible chromatin with high-throughput sequencing, and expression profiling through RNA sequencing, reveals global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment, and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.

Keywords:  H3K9/H3K36 demethylation; KDM4; age‐related pathology; aging; cellular senescence; epigenetic modification

DOI:  https://doi.org/10.1111/acel.70194
Mol Metab. 2025 Aug 21. pii: S2212-8778(25)00143-7. [Epub ahead of print]100 102236

Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction.

Seokwon Jo, Grace Chung, Yu-Jin Youn, Charlotte Hunt, Ava Hill, Megan Beetch, Brian Akhaphong, Elizabeth A Morgan, Perrie F O'Tierney-Ginn, Sarah A Wernimont, Emilyn U Alejandro.

  Mitochondria are crucial for regulating metabolism, but their role in the placenta and how they may shape offspring metabolism and long-term health remains unclear, despite being commonly associated with pregnancy complications. To investigate this, we used a genetic model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO) and assessed the metabolic trajectory of adult offspring. We found that, at baseline, female placental trophoblasts in wild-type animals exhibited higher respiration rates than males. MCU deletion impaired mitochondrial function specifically in female placentas and was accompanied by distinct changes in the metabolomic profiles of protein and lipid metabolism. Transcriptome analysis revealed reduced placental cellular growth pathways, consistent with smaller placentas and reduced embryonic body weights in Pl-MCUKO. Although in utero MCU deletion affected fetal growth, it was insufficient to cause permanent postnatal changes in body weight, as these deficits normalized in adulthood, with normal glucose homeostasis in Pl-MCUKO offspring. However, when challenged with a high-fat diet, Pl-MCUKO females exhibited reduced weight gain, improved glucose and insulin tolerance, smaller fat depots, and increased ambulatory activity compared to controls. This improved metabolic profile was associated with reduced pancreatic β-cell mass but preserved β-cell function. These findings provide direct evidence that placental mitochondrial function can influence the long-term metabolic health of female offspring by modulating key metabolic tissues.

Keywords:  DOHaD; Metabolic health; Mitochondria; Mitochondrial calcium uniporter; Obesity; Placenta; Sexual dimorphism

DOI:  https://doi.org/10.1016/j.molmet.2025.102236
Nat Commun. 2025 Aug 20. 16(1): 7438

Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.

Jeremy Williams, Roman Camarda, Serghei Malkov, Lisa J Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Van de Mark, Rachel Nakagawa, Yong Chen, Charles Berdan, Sharon M Louie, Celine Mahieu, Daphne Superville, Juliane Winkler, Elizabeth Willey, Erica J Hutchins, John D Gagnon, Seda Kilinc Avsaroglu, Kosaku Shinoda, Matthew Gruner, Hiroshi Nishida, K Mark Ansel, Zena Werb, Daniel K Nomura, Shingo Kajimura, Atul J Butte, Melinda E Sanders, Daniel C Liebler, Hope S Rugo, Gregor Krings, John A Shepherd, Andrei Goga.

A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.

DOI: https://doi.org/10.1038/s41467-025-62486-3
Saudi Pharm J. 2025 Aug 26. 33(5): 31

Talazoparib and radiation enhance the senolytic efficacy of venetoclax in therapy-induced senescent triple-negative breast cancer cells.

Sultan Almudimeegh, Mashal M Almutairi, Abrar Softah, Khalid Alhazzani, Lama Binobaid, Musaad Alshammari, Homood M As Sobeai, Tareq Saleh, Moureq R Alotaibi, Ali Alhoshani.

  Triple-negative breast cancer (TNBC) presents ongoing clinical challenges, often leading to relapse in many patients. The relapse is partly explained by tumor cells transitioning into a senescent state following chemotherapy or radiation, resulting in a more aggressive phenotype, contributing to disease recurrence. Consequently, combining senolytics with traditional treatments could be a viable and promising strategy in treating TNBC. To address this, we induced therapy-induced senescence (TIS) both in vitro and in vivo by combining the poly ADP-ribose polymerase (PARP) inhibitor talazoparib with radiation. We tested whether exposure to the senolytic agent, venetoclax, would result in the eradication of senescent cells and augmentation of apoptosis. TIS Markers, like senescence-associated beta-galactosidase (SA-β-gal), CDKN1A, and senescence-associated secretory phenotype (SASP) marker IL-6, were altered following talazoparib and radiation in both 4T1 and MDA-MB-231 TNBC cell lines. Interestingly, venetoclax treatment following TIS induction led to pronounced apoptotic cell death and significant changes in SA-β-gal and IL-6, implying enhanced sensitivity post-senescence induction. Furthermore, these data were validated in vivo in an immunocompetent TNBC-bearing mouse model, in which venetoclax alone had a modest effect on growth inhibition. However, when combined with radiotherapy/talazoparib, venetoclax dramatically interfered with tumor recovery post-senescence induction, indicating a potential strategy to mitigate disease recurrence. These results suggest that combining radiotherapy with PARP inhibitors with senolytic agents such as venetoclax could potentially overcome disease relapse associated with TNBC.

Keywords:  PARPi; Radiotherapy (Min.5-Max. 8); Senescence; TNBC; Venetoclax

DOI:  https://doi.org/10.1007/s44446-025-00034-2
Biomater Sci. 2025 Aug 26.

Real-time monitoring of mitochondrial temperature and calcium spikes using fluorescent organic probes.

Mengnan Sun, Bo Chen, Aiguo Wu.

Astrocytes, the abundant glial cells, maintain cerebral homeostasis and cognitive functions through calcium signalling - a regulatory pathway that is frequently altered in brain disease. Mitochondria serve as thermal hubs in living systems, generating metabolic heat during respiratory substrate oxidation and ATP synthesis. Crucially, mitochondrial temperature variations directly reflect metabolic status, as impaired ATP production induces thermodynamic shifts. Here, we utilized a fluorescent thermometer probe MTY for in vitro determination and visualization of intracellular mitochondrial temperatures at the single-cell level. Through precisely controlled thermal modulation of fixed, living, and laser-stimulated astrocytes, we established a platform extendable to MCF-7 and Panc02 cell lines. The methodology enabled real-time tracking of near-infrared-induced thermal perturbations and FCCP-mediated uncoupling effects. Spinning-disk confocal microscopy revealed synchronized mitochondrial thermogenesis and calcium transients, with thermal/laser stimulation inducing 2-4-fold greater calcium spiking versus controls. Mechanistic analysis suggested this response was likely mediated through TRPV4 channel-mediated extracellular Ca2+ influx and/or intracellular calcium release from mitochondrial and endoplasmic reticulum stores.

DOI: https://doi.org/10.1039/d5bm00691k
J Invest Dermatol. 2025 Aug 19. pii: S0022-202X(25)02345-0. [Epub ahead of print]

Oxidative fragmentation of collagen in skin - relevance to skin aging and skin diseases.

Vendula Paculová, Ankush Prasad, Pavel Pospíšil.



Keywords:  collagen fragmentation; oxidative stress; protein carbonylation; skin aging; β-scission

DOI:  https://doi.org/10.1016/j.jid.2025.08.005
Exp Physiol. 2025 Aug 25.

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

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

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

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

DOI:  https://doi.org/10.1113/EP092977
Genes (Basel). 2025 Aug 11. pii: 948. [Epub ahead of print]16(8):

Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance.

Angelina Titova, Airat Bilyalov, Nikita Filatov, Stepan Perepechenov, Darya Kupriyanova, Sergei Brovkin, Dmitrii Shestakov, Natalia Bodunova, Oleg Gusev.

  Sarcopenia, the progressive loss of skeletal muscle mass and function with age, significantly contributes to frailty and mortality in older adults. Notably, muscles do not age uniformly-some retain structure and strength well into old age. This review explores the mechanisms underlying differential resistance to muscle aging, with a focus on sarcopenia-resistant muscles. We analyzed current literature across molecular biology, genetics, and physiology to identify key regulators of muscle preservation during aging. Special attention was given to muscle fiber types, mitochondrial function, neuromuscular junctions, and satellite cell activity. Muscles dominated by slow-twitch (type I) fibers-such as the soleus, diaphragm, and extraocular muscles-demonstrate enhanced resistance to sarcopenia. This resilience is linked to sustained oxidative metabolism, high mitochondrial density, robust antioxidant defenses, and preserved regenerative capacity. Key molecular pathways include mTOR, PGC-1α, and SIRT1/6, while genetic variants in ACTN3, MSTN, and FOXO3 contribute to interindividual differences. In contrast, fast-twitch muscles are more vulnerable due to lower oxidative capacity and satellite cell depletion. Unique innervation patterns and neurotrophic support further protect muscles like extraocular muscles from age-related atrophy. Resistance to sarcopenia is driven by a complex interplay of intrinsic and extrinsic factors. Understanding why specific muscles age more slowly provides insights into muscle resilience and suggests novel strategies for targeted prevention and therapy. Expanding research beyond traditionally studied muscles is essential to develop comprehensive interventions to preserve mobility and independence in aging populations.

Keywords:  muscle atrophy; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.3390/genes16080948
Exp Cell Res. 2025 Aug 20. pii: S0014-4827(25)00321-0. [Epub ahead of print]451(2): 114721

Cancer as a failed response to renegade mitochondria.

John Hartung.

  In 1948, before the word 'mitochondrion' gained common parlance in the lexicon of cell biologists, Cyril Darlington published The Plasmagene Theory of the Origin of Cancer without referring to mitochondria per se. Reconsideration of Darlington's theory is warranted today because discoveries about the extraordinary capacities of mitochondria - the organelles that house Darlington's "plasmagenes" - have grown exponentially. If Darlington was right, if intracellular competition between mutant and wild-type mitochondria is the first cause of cancer, it may be the case that a general cure for cancer will include injection of: (A) nanoparticles carrying wild-type mitochondrial genes, and (B) copious amounts of wild-type mitochondria.

Keywords:  Apoptosis; Cancer; Evolution; Experiment; Heteroplasmic; Homoplasmic; Mitochondria; Mitochondrial transfer; Mitophagy; Reproductive competition; Reversible reaction

DOI:  https://doi.org/10.1016/j.yexcr.2025.114721
Nature. 2025 Sep;645(8079): 19-20

Repeated heatwaves can age you as much as smoking or drinking.

Freda Kreier.



Keywords:  Ageing; Climate change; Public health

DOI:  https://doi.org/10.1038/d41586-025-02729-x
Nat Commun. 2025 Aug 26. 16(1): 7961

Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle.

Shanshan Liu, Yu Ji, Luyang Wei, Yiqiao Zhang, Linghang Zeng, Yiyang Min, Danyang Yin, Kun Liu, Chengjian Guan, Shumeng Liu, Huajing Yu, Zhongtao Zhang.

Metabolic dysfunction-associated steatotic liver disease (MASLD), potentially ameliorated by bariatric-metabolic surgery, remains a global health concern in the absence of approved drugs. Protein post-translational modifications (PTMs) are crucial for MASLD. However, the functional significance of lysine crotonylation (Kcr) remains unclear. We aimed to investigate the mechanisms by Kcr-regulated IDH1 in the tricarboxylic acid (TCA) cycle and MASLD development. Herein, we reported a quantitative proteomics analysis of global crotonylome upon MASLD and Post-bariatric. Specifically, decreases in K58cr, K151cr, K212cr and K345cr of IDH1 upon MASLD were observed. PCAF and SIRT7 dynamically regulated the IDH1 Kcr. Abolishment of IDH1 Kcr impaired TCA cycle by decreasing IDH1 enzymatic activity. Male mice with liver-specific expression of crotonylation-mimic mutants of IDH1 were resistant to HFD-induced obesity, insulin resistance, glucose intolerance and MASLD. Our findings unravel the mechanisms of IDH1 Kcr and indicate that targeting PCAF/SIRT7-IDH1 Kcr and metabolites may be a promising strategy for MASLD therapy.

DOI: https://doi.org/10.1038/s41467-025-62731-9
Nat Chem Biol. 2025 Aug 22.

α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.

Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.

DOI: https://doi.org/10.1038/s41589-025-02013-z
Skelet Muscle. 2025 Aug 22. 15(1): 22

NAD+ dyshomeostasis in RYR1-related myopathies.

Tokunbor A Lawal, Willa Riekhof, Linda Groom, Pooja Varma, Irene C Chrismer, Angela Kokkinis, Christopher Grunseich, Jessica W Witherspoon, Muslima S Razaqyar, Ninet Sinaii, Katherine G Meilleur, Lichen Xiang, Jana Buzkova, Liliya Euro, Payam Mohassel, Robert T Dirksen, Joshua J Todd.

   BACKGROUND: Pathogenic variants in RYR1 cause a spectrum of rare congenital myopathies associated with intracellular calcium dysregulation. Glutathione redox imbalance has been reported in several Ryr1 disease model systems and clinical studies. NAD+ and NADP are essential cofactors in cellular metabolism and redox homeostasis. NAD+ deficiency has been associated with skeletal muscle bioenergetic deficits in mitochondrial myopathy and sarcopenia.
METHODS: Using a new colorimetric assay and large control dataset (n = 299), we assessed redox balance (glutathione, NAD+, and NADP) in whole blood from 28 RYR1-RM affected individuals (NCT02362425). Analyses were expanded to human skeletal muscle (n = 4), primary myotube cultures (n = 5), and whole blood and skeletal muscle specimens from Ryr1 Y524S mice. The in vitro effects of nicotinamide riboside (NR) on cellular NAD+ content and mitochondrial respirometry were also tested.
RESULTS: At baseline, a majority of affected individuals exhibited systemic NAD+ deficiency (19/28 [68%] < 21 µM) and increased NADPH concentrations (22/26 [85%] > 1.6 µM). When compared to controls, decreased NAD+/NADH and NADP/NADPH ratios were observed in 9/28 and 23/26 individuals, respectively. In patient-derived myotube cultures (n = 5), NR appeared to increase cellular NAD+ concentrations in a dose and time-dependent manner at 72-h only and favorably modified maximal respiration and ATP production. Average whole blood GSH/GSSG ratio was comparable between groups, and redox imbalance was not observed in Ryr1 Y524S specimens.
CONCLUSIONS: NAD+ and NADP dyshomeostasis was identified in a subset of RYR1-RM affected individuals. Further experiments are warranted to confirm if NAD+ repletion could be an attractive therapeutic approach given the favorable outcomes reported in other neuromuscular disorders.

Keywords:   RYR1 ; Congenital myopathy; Glutathione; NAD+ ; NADP; Oxidative stress

DOI:  https://doi.org/10.1186/s13395-025-00390-6
Brain Sci. 2025 Aug 19. pii: 884. [Epub ahead of print]15(8):

Redox-Regulated Pathways in Glioblastoma Stem-like Cells: Mechanistic Insights and Therapeutic Implications.

Nadia Fernanda Esteban-Román, Elisa Taddei, Edson Castro-Velázquez, Lorna Villafuentes-Vidal, Alejandra Velez-Herrera, Moisés Rubio-Osornio, Carmen Rubio.

  Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance.

Keywords:  cancer stem cells; glial stem-like cells; glioblastoma; glioma; oxidative stress; redox-targeted therapy

DOI:  https://doi.org/10.3390/brainsci15080884
Aging (Albany NY). 2025 Aug 25. 17

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

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

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

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

DOI:  https://doi.org/10.18632/aging.206305
Nat Commun. 2025 Aug 22. 16(1): 7811

Dual-key cooperatively activated DNA regulator for controlling mitochondria-lysosome interactions.

Yang Xiao, Longyi Zhu, Songyuan Du, Xinyi Ge, Lequn Ma, Shengyuan Deng, Kewei Ren.

Mitochondria-lysosome interactions are critical for maintaining cellular homeostasis. Although genetically encoded protein based optogenetic technique is developed to regulate such interactions, it still suffers from shortcomings including complicated operation and potential interference to organelle functions. Here, we present a fast, simple, biocompatible and programmable platform via activable DNA regulators to achieve spatiotemporal regulation of mitochondria-lysosome interactions in living cells. In our system, two locked DNA regulators, OK-MLIR and DK-MLIR, that can be respectively activated with UV light (One Key) as well as UV light and endogenous glutathione (Dual Keys), are modularly designed for modulating mitochondria-lysosome contacts. We show that these DNA regulators can be used for facilitating mitochondrial fission and autophagy. Moreover, the DK-MLIR enables selective and efficient manipulation of target cell migration and proliferation with highly temporal and spatial controllability. This programmable and modular design principle provides a platform for organelle interaction study, cellular regulation and precision therapy.

DOI: https://doi.org/10.1038/s41467-025-63040-x
J Geriatr Oncol. 2025 Aug 19. pii: S1879-4068(25)00162-6. [Epub ahead of print]16(8): 102346

Aging-related, senescence-associated secretory phenotype and allogeneic hematopoietic cell transplantation outcomes in older patients.

Mark Y Jeng, Phillip Wong, Jessica R Flynn, Erika Ritter, Caleb Ho, Josel D Ruiz, Ann A Jakubowski, Esperanza B Papadopoulos, Brian C Shaffer, Doris R Ponce, Roni Tamari, James W Young, Miguel Angel-Perales, Sean Devlin, Sergio A Giralt, Richard J Lin.



Keywords:  Aging biomarkers; Allogeneic transplant; Geriatric oncology; Myeloid malignancies; SASP; Senescence

DOI:  https://doi.org/10.1016/j.jgo.2025.102346
Cell Death Dis. 2025 Aug 26. 16(1): 646

MRPL12 K163 acetylation inhibits ccRCC via driving mitochondrial metabolic reprogramming.

Xingzhao Ji, Fuyuan Xue, Ying Wang, Dexuan Gao, Jian Sun, Tianyi Dong, Qian Mu, Quanlin Xu, Shengnan Sun, Yi Liu, Qiang Wan.

Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12's binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.

DOI: https://doi.org/10.1038/s41419-025-07896-3
Biochem Biophys Res Commun. 2025 Aug 23. pii: S0006-291X(25)01243-4. [Epub ahead of print]781 152528

TRAP1 promotes self-renewal and tumorigenicity of glioblastoma stem cells by inhibiting Notch1 ubiquitination.

Ming Feng, Xiao Zhang, Youxin Zhou.

  Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system and is classified as Grade IV in the World Health Organization (WHO)'s brain tumor categorization. Even with standard treatment protocols, the median overall survival of newly diagnosed GBM patients is only 14.6 months. Glioblastoma stem cells (GSCs), a small subset of GBM cells with self-renewal and multilineage differentiation capacities, are considered critical contributors to the strong tumor heterogeneity, diffuse progression, and recurrence of GBM. Investigating signaling pathways associated with GSCs to identify novel therapeutic strategies targeting these cells is of paramount importance. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the 90 kDa heat shock protein (Hsp90) family, has been implicated in the maintenance or regulation of GSC stemness. However, its underlying mechanisms remain poorly understood. In this study, we demonstrated that TRAP1 is highly expressed in GSCs and that its elevated expression correlates with enhanced self-renewal capacity and in vivo tumorigenicity of GSCs. Mechanistically, TRAP1 interacts with Notch1 and inhibits its ubiquitination, thereby promoting GSC stemness. Knockdown of TRAP1 expression reduced the self-renewal capacity and in vivo tumorigenicity of GSCs, consequently improving the prognosis of tumor-bearing mice. These findings suggest that targeting TRAP1 may represent a viable strategy to improve outcomes for glioblastoma patients in the future.

Keywords:  Glioblastoma stem cells; Notch1; Self-renewal; TRAP1; Tumorigenicity; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbrc.2025.152528
Pharmaceuticals (Basel). 2025 Jul 22. pii: 1080. [Epub ahead of print]18(8):

α-Ketoglutarate Attenuates Oxidative Stress-Induced Neuronal Aging via Modulation of the mTOR Pathway.

Ruoqing Guan, Zhaoyun Xue, Kaikun Huang, Yanqing Zhao, Gongyun He, Yuxing Dai, Mo Liang, Yanzi Wen, Xueshi Ye, Peiqing Liu, Jianwen Chen.

  Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H2O2-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD+/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H2O2-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG's anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases.

Keywords:  D-galactose; H2O2; TCA; alpha-ketoglutarate; brain aging; mTOR; proteomic

DOI:  https://doi.org/10.3390/ph18081080
Dietetics (Basel). 2025 Sep;pii: 32. [Epub ahead of print]4(3):

Branched-Chain Amino Acids Combined with Exercise Improves Physical Function and Quality of Life in Older Adults: Results from a Pilot Randomized Controlled Trial.

Ronna Robbins, Jason C O'Connor, Tiffany M Cortes, Monica C Serra.

  This pilot, randomized, double-blind, placebo-controlled trial investigated the effects of branched-chain amino acids (BCAAs)-provided in a 2:1:1 ratio of leucine:isoleucine: valine-combined with exercise on fatigue, physical performance, and quality of life in older adults. Twenty participants (63% female; BMI: 35 ± 2 kg/m2; age: 70.5 ± 1.2 years) were randomized to 8 weeks of either exercise + BCAAs (100 mg/kg body weight/d) or exercise + placebo. The program included moderate aerobic and resistance training three times weekly. Physical function was assessed using handgrip strength, chair stands, gait speed, VO2 max, and a 400 m walk. Psychological health was evaluated using the CES-D, Fatigue Assessment Scale (FAS), Insomnia Severity Index (ISI), and global pain, fatigue, and quality of life using a visual analog scale (VAS). Significant group x time interactions were found for handgrip strength (p = 0.03), chair stands (p < 0.01), and 400 m walk time (p < 0.01). Compared to exercise + placebo, exercise + BCAAs showed greater improvements in strength, mobility, and endurance, along with reductions in fatigue (-45% vs. +92%) and depressive symptoms (-29% vs. +5%). Time effects were also observed for ISI (-30%), FAS (-21%), and VAS quality of life (16%) following exercise + BCAA supplementation. These preliminary results suggest that BCAAs combined with exercise may be an effective way to improve physical performance and reduce fatigue and depressive symptoms in older adults.

Keywords:  branched-chain amino acids; exercise; fatigue; older adults; physical functioning

DOI:  https://doi.org/10.3390/dietetics4030032