bims-cesemi 2025-09-28 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–09–28
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels.
TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
Mitochondrial Ca2+ in Cancer Growth and Metabolism.
Targeting the Mitochondria in High-Grade Gliomas.
CDK12 regulates cellular metabolism to promote glioblastoma growth.
VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy.
Lysosomes signal through the epigenome to regulate longevity across generations.
Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.
Therapy-induced senescence in prostate cancer: Mechanisms, therapeutic strategies, and clinical implications.

Aging Cell. 2025 Sep 26. e70247

Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels.

Doruntina Bresilla, Ines Tawfik, Martin Hirtl, Sonja Gabrijelčič, Julian Ostaku, Fabienne Mossegger, Lia Wurzer, Susanne Lederer, Katarina Kalinova, Ernst Malle, Markus Schosserer, Kim Zarse, Michael Ristow, Corina T Madreiter-Sokolowski.

  Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival. This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels. Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.

Keywords:   C. elegans ; aging; lifespan; longevity; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1111/acel.70247
bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.

Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

DOI: https://doi.org/10.1101/2025.09.11.675705
J Cell Physiol. 2025 Sep;240(9): e70093

Mitochondrial Ca2+ in Cancer Growth and Metabolism.

Jillian S Weissenrieder, J Kevin Foskett.

  Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that underlie malignancy will enable us to develop more effective therapeutic options to improve patient outcomes. One particular area of interest is in cancer cell metabolism. Even as early as the 1920s, Otto Warburg recognized dysregulated metabolism in cancerous cells. Altered metabolism may provide targetable nutrient dependencies for further clinical development, either by nutrient restriction or pathway inhibition. More recently, researchers have observed an increasingly strong linkage between altered mitochondrial Ca2+ homeostasis and tumor cell metabolism, with strong implications for therapeutic targeting. In this review, we summarize the literature surrounding mitochondrial Ca2+ homeostasis, metabolism, and cancer, as well as providing a discussion of the potential for mitochondrial Ca2+ modulation as an anticancer therapeutic modality.

Keywords:  Ca2+ signaling; cancer; metabolism; mitochondria

DOI:  https://doi.org/10.1002/jcp.70093
Cancers (Basel). 2025 Sep 19. pii: 3062. [Epub ahead of print]17(18):

Targeting the Mitochondria in High-Grade Gliomas.

Shaunak Sathe, Qi Li, Jinkyu Jung, Jing Wu.

  High-grade gliomas are aggressive primary brain tumors and often fatal. They are characterized by rapid growth, treatment resistance, and significant heterogeneity both within and between tumors. A growing body of evidence highlights the mitochondria, dynamic organelles essential for energy production, apoptosis regulation, and metabolic rewiring, as a critical driver in glioma progression and treatment resistance. As a result, these insights have sparked growing interest in mitochondrial-directed therapies. This review highlights the distinct metabolic features and mitochondrial processes of glioma, outlining the rationale for targeting mitochondrial function. We discuss recent advances in mitochondrial-targeted therapies, with a focus on caseinolytic protease P (ClpP) agonism as a breakthrough in the treatment of diffuse midline glioma (DMG). Moreover, we discuss the pathogenic link between mitochondrial metabolism and epigenetic regulation, and the potential therapeutic benefit of disrupting this interaction.

Keywords:  DMG; clinical trial; glioblastoma; high-grade glioma; mitochondria

DOI:  https://doi.org/10.3390/cancers17183062
JCI Insight. 2025 Sep 25. pii: e190780. [Epub ahead of print]

CDK12 regulates cellular metabolism to promote glioblastoma growth.

Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Zhe Zhu, Hasan O Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patientderived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³Cglutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12-GSK3β-PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.

Keywords:  Apoptosis; Brain cancer; Metabolism; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.190780
Int J Mol Sci. 2025 Sep 11. pii: 8845. [Epub ahead of print]26(18):

VBIT-4 Rescues Mitochondrial Dysfunction and Reduces Skeletal Muscle Degeneration in a Severe Model of Duchenne Muscular Dystrophy.

Mikhail V Dubinin, Anastasia E Stepanova, Irina B Mikheeva, Anastasia D Igoshkina, Ekaterina N Kraeva, Alena A Cherepanova, Eugeny Yu Talanov, Anna V Polikarpova, Maxim E Astashev, Vyacheslav A Loginov, Tatiana V Egorova.

  Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration and fibrosis. A key pathological feature of DMD is mitochondrial dysfunction driven by calcium overload, which disrupts oxidative phosphorylation and triggers cell death pathways. This study shows the therapeutic potential of VBIT-4, a novel inhibitor of the mitochondrial voltage-dependent anion channel (VDAC), in two dystrophin-deficient mouse models: the mild mdx and the severe D2.DMDel8-34 strains. VBIT-4 administration (20 mg/kg) reduced mitochondrial calcium overload, enhanced resistance to permeability transition pore induction, and improved mitochondrial ultrastructure in D2.DMDel8-34 mice, while showing negligible effects in mdx mice. VBIT-4 suppressed mitochondrial and total calpain activity and reduced endoplasmic reticulum stress markers, suggesting a role in mitigating proteotoxic stress. However, it did not restore oxidative phosphorylation or reduce oxidative stress. Functional assays revealed limited improvements in muscle strength and fibrosis reduction, exclusively in the severe model. These findings underscore VDAC as a promising target for severe DMD and highlight the critical role of mitochondrial calcium homeostasis in DMD progression.

Keywords:  Duchenne muscular dystrophy; VBIT-4; VDAC; calcium overload; proteotoxic stress; skeletal muscle mitochondria

DOI:  https://doi.org/10.3390/ijms26188845
Science. 2025 Sep 25. 389(6767): 1353-1360

Lysosomes signal through the epigenome to regulate longevity across generations.

Qinghao Zhang, Weiwei Dang, Meng C Wang.

The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic target of rapamycin (mTOR) signaling increased the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germ line to mediate transgenerational inheritance of longevity.

DOI: https://doi.org/10.1126/science.adn8754
Adv Sci (Weinh). 2025 Sep 24. e07759

Mitochondria-Localized Nestin Protects Mesenchymal Stem Cells from Senescence by Maintaining Cristae Structure and Function.

Hainan Chen, Jinsi Chen, Li Huang, Xingqiang Lai, Kai Xia, Qiying Lu, Bingbing Xie, Yinong Huang, Yuan Qiu, Tao Wang, Jianqi Feng, Yuanjun Guan, Siyao Che, Jiancheng Wang, Andy Peng Xiang.

  Nestin, a well-characterized intermediate filament protein expressed in stem cells, is increasingly recognized for its non-canonical roles in diverse subcellular compartments. Here, a novel mitochondrial localization of Nestin in human mesenchymal stem cells (hMSCs) is identified, where it functions as a critical protector against mitochondrial dysfunction and cellular senescence. It is demonstrated that Nestin is imported into the mitochondrial intermembrane space via its N-terminal mitochondrial targeting sequence through Translocase of the Outer Mitochondrial Membrane 20 (TOM20)-dependent machinery. Within mitochondria, Nestin directly interacts with Mic60 to maintain cristae architecture and sustain oxidative phosphorylation. Genetic ablation of mitochondrial Nestin triggers cristae disorganization, respiratory deficiency, and premature senescence in hMSCs. Strikingly, targeted restoration of the Mic60-binding Tail3 domain of Nestin is sufficient to rescue cristae morphology, mitochondrial function, and senescence phenotypes. These findings establish a non-filamentous role for Nestin in mitochondrial quality control and propose a new therapeutic strategy for age-related disorders through modulation of mitochondrial Nestin-Mic60 interactions.

Keywords:  Cellular senescence; Mic60; Mitochondria; Nestin; human mesenchymal stem cells (hMSCs)

DOI:  https://doi.org/10.1002/advs.202507759
Gene. 2025 Sep 22. pii: S0378-1119(25)00563-3. [Epub ahead of print] 149774

Therapy-induced senescence in prostate cancer: Mechanisms, therapeutic strategies, and clinical implications.

Luisa Bacca, Julian Brandariz, Francesca Zacchi, Andrea Zivi, Joaquin Mateo, David P Labbé.

  Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, particularly in its advanced and metastatic stages. While various systemic therapies have improved clinical outcomes, therapy resistance and disease progression remain significant challenges. One critical, yet underappreciated, mechanism influencing treatment response is therapy-induced senescence (TIS), a stable form of cell cycle arrest triggered by anticancer treatments. In PCa, TIS can be elicited by chemotherapy, radiotherapy, hormonal therapies, and targeted agents, and is characterized by a complex interplay of tumor-suppressive and tumor-promoting effects, largely mediated through the senescence-associated secretory phenotype (SASP). This review explores the molecular mechanisms of senescence, the diverse therapeutic strategies that induce it, and the dual roles it plays in PCa progression and treatment resistance. We further discuss emerging approaches that combine senescence-inducing therapies with senescence-targeting strategies, such as senolytics and senomorphics, to mitigate the adverse consequences of persistent senescent PCa cells. Finally, we highlight ongoing clinical trials, translational barriers, and future directions in integrating senotherapy into the clinical management of PCa.

Keywords:  Cellular senescence; Prostate cancer; Senescence-associated secretory phenotype (SASP); Therapy-induced senescence (TIS)

DOI:  https://doi.org/10.1016/j.gene.2025.149774