bims-cesemi 2025-09-07 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–09–07
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor

Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
ODC-Driven Polyamines Synthesis Sustains the Self-Renewal of Glioblastoma Stem Cells and Drives Tumor Aggressiveness.
Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.
Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.
Daily briefing: Epigenetic atlas shows how ageing tweaks DNA.
Protein Acetylation and NAD+ Homeostasis in Aging Muscle.
Lactobacillus amylovorus KU4 inhibits adipocyte senescence in aged mice through necdin regulation of p53 activity.
β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
Substrate stiffness and viscoelasticity influence fibroblast senescence.
Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.
Anabolic and anticatabolic actions of ketone bodies on skeletal muscle: potential relevance in the management of skeletal muscle wasting.
Unlocking longevity through the comparative biology of aging.

Mol Cancer Ther. 2025 Sep 05. OF1-OF13

Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.

Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley.

Diffuse mesothelioma is a rare but highly aggressive and treatment-resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid cell leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells, and patient-derived xenografts (PDX) by B-cell homology domain-3 profiling; we observed striking consistency which enabled cross-model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging noncanonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency, rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its antiapoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2-targeted therapy to undermine therapeutic resistance in patients with diffuse mesothelioma.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0873
Cancer Sci. 2025 Aug 28.

ODC-Driven Polyamines Synthesis Sustains the Self-Renewal of Glioblastoma Stem Cells and Drives Tumor Aggressiveness.

Xue-Chen Wei, Hao-Qian Zhang, Guang-Qin Liu, Chang-Wei Liu, Ai-Ling Li, Xin Pan, Wei-Qun Yan, Jia-Yi Chen.

  Glioblastoma stem cells (GSCs) are crucial drivers of tumor progression and therapeutic resistance in glioblastoma multiforme (GBM), yet the molecular mechanisms maintaining their self-renewal remain incompletely understood. Here, we identify a critical role for polyamine metabolism in GSCs maintenance. We show that GSCs exhibit elevated polyamine levels compared to non-stem tumor cells, attributed to enhanced ornithine decarboxylase (ODC) expression. High ODC expression correlates with poor patient prognosis in GBM. Genetic and pharmacologic targeting of ODC attenuated GSCs self-renewal and tumorigenicity. Our findings reveal a previously unrecognized metabolic dependency of GSCs on polyamine synthesis, and ODC may be a potential therapeutic target in GBM.

Keywords:  CRISPR‐Cas9; glioblastoma stem cells; ornithine decarboxylase; polyamine metabolism; therapeutic target

DOI:  https://doi.org/10.1111/cas.70182
EMBO Rep. 2025 Aug 29.

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.

Tak Shun Fung, Amrapali Ghosh, Maite R Zavala, Zuzana Nichtova, Dhavalkumar Shukal, Marco Tigano, Gyorgy Csordas, Henry N Higgs, Rajarshi Chakrabarti.

  Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin

DOI:  https://doi.org/10.1038/s44319-025-00561-y
FEBS J. 2025 Aug 28.

Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.

Samrat Chakraborty, Raz Ben-David, Shenhav Shemer.

  Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophies, motor-neuron diseases, cancer, type-2 diabetes, or aging-have detrimental effects on human health, reducing quality of life and survival. Currently, exercise is the only validated treatment for increasing muscle mass and function, but it is impractical for bedridden patients or the frail elderly. Significant advances in understanding the molecular mechanisms underlying atrophy of slow- or fast-twitch muscle fibers have identified numerous previously unknown key players that may show promise as potential drug targets. Here, we review these recent advances and discuss the potential of these discovered mechanisms as therapeutic targets to combat muscle wasting.

Keywords:  fiber type; muscle atrophy; myosin; skeletal muscle; therapeutic targets

DOI:  https://doi.org/10.1111/febs.70241
Nature. 2025 Sep 02.

Daily briefing: Epigenetic atlas shows how ageing tweaks DNA.

Flora Graham.

DOI: https://doi.org/10.1038/d41586-025-02832-z
Adv Exp Med Biol. 2025 ;1478 421-443

Protein Acetylation and NAD+ Homeostasis in Aging Muscle.

Li Li Ji.

  Hyperacetylation of proteins represents a stress to aged organisms. Increased consumption and loss of NAD+ homeostasis underlie a major mechanism for the disturbed acetylation/deacetylation balance during aging. Nicotinamide adenine dinucleotide (NAD) is a versatile chemical compound serving as a coenzyme in metabolic pathways and as a substrate to support the enzymatic functions of sirtuins (SIRTs), poly (ADP-ribose) polymerase-1 (PARP-1), and cyclic ADP ribose hydrolase (CD38). Under normal physiological conditions, NAD+ consumption is matched by its synthesis primarily via the salvage pathway catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). However, aging and muscular contraction enhance NAD+ utilization, whereas NAD+ replenishment is limited by cellular sources of NAD+ precursors and/or enzyme expression. This chapter will briefly review NAD+ metabolic functions, its roles in regulating cell signaling, mechanisms of its degradation and biosynthesis, and major challenges to maintain its cellular level in skeletal muscle. The effects of aging, physical exercise, and dietary supplementation on NAD+ homeostasis will be highlighted based on recent literature.

Keywords:  Acetylation; Aging; Exercise; NAD+; Sirtuin; Skeletal muscle

DOI:  https://doi.org/10.1007/978-3-031-88361-3_17
Aging (Albany NY). 2025 Sep 03. 17

Lactobacillus amylovorus KU4 inhibits adipocyte senescence in aged mice through necdin regulation of p53 activity.

Garam Yang, Eunjeong Hong, Hyuno Kang, Sejong Oh, Eungseok Kim.

  Previously, we reported that Lactobacillus amylovorus KU4 (LKU4) ameliorates diet-induced metabolic disorders by regulating adipose tissue (AT) physiology. Since metabolic disorders and age-related pathological conditions mutually exacerbate each other, this study hypothesizes that LKU4 may protect against adipose senescence during aging. Thus, this study demonstrates that LKU4 administration suppresses age-related metabolic dysfunction and aging phenotypes in AT of 24-month-old mice. Furthermore, LKU4 suppressed the expression of senescence marker genes, including p53, in the AT of these mice in parallel with the upregulation of necdin (NDN). Particularly, the effect of LKU4 on the expression of these genes was enhanced in adipocytes compared to stromal vascular fraction (SVF) cells. Mechanistically, NDN mediates the LKU4-induced suppression of p53 transcriptional activity by blocking the p53-p300 interaction, thereby inhibiting p53 acetylation. Both LKU4 and NDN consistently reduced the senescence-associated secretory phenotype (SASP) in the AT of aged mice and senescent 3T3-L1 adipocytes. Furthermore, ex vivo NDN silencing in the AT of D-galactose-induced aging mice abolished LKU4 protection against p53-induced adipose senescence, reducing adipogenesis and mitochondrial dysfunction in primary adipocytes. These findings demonstrate that LKU4 inhibits age-induced adipocyte senescence by modulating the p53-p300 interaction through NDN, thereby protecting against age-associated metabolic disorders.

Keywords:  Lactobacillus amylovorus KU4; adipocyte senescence; aging; necdin; p53

DOI:  https://doi.org/10.18632/aging.206314
J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636

β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.

Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.

  Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.

Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation

DOI:  https://doi.org/10.1016/j.jbc.2025.110636
bioRxiv. 2025 Aug 27. pii: 2025.08.22.671571. [Epub ahead of print]

Substrate stiffness and viscoelasticity influence fibroblast senescence.

Mackenzie L Skelton, Tanvi Bhat, Ethan Yu, Afia Ofori, Steven R Caliari.

Senescent cell accumulation has been implicated in aging and fibrotic disease, which are both characterized by increased tissue stiffness. However, the direct connection between tissue mechanics and senescence induction remains disputed in the literature. Thus, this work investigates the influence of hydrogel stiffness and viscoelasticity in promoting fibroblast senescence both in combination with genotoxic stress and independently. We show that while lung fibroblast YAP signaling declines with senescence induction, senescent fibroblasts maintain their mechanosensing capabilities with increased YAP nuclear localization on higher stiffness hydrogels. Most notably, we find a unique role for hydrogel viscoelasticity in senescence induction with soft (2 kPa) viscoelastic substrates promoting both the onset and amplification of senescence, even in the absence of genotoxic stress. These changes are not associated with a decline in YAP activity, but instead with a decline in nuclear DAPI intensity, suggesting a role of nuclear organization in driving this phenotype. Overall, this work highlights the influence of mechanics on the induction of senescence and supports the key role of viscoelasticity.

DOI: https://doi.org/10.1101/2025.08.22.671571
bioRxiv. 2025 Aug 30. pii: 2025.08.27.672709. [Epub ahead of print]

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.

Utkarsh Tripathi, Masayoshi Suda, Vagisha Kulshreshtha, Bryan T Piatkowski, Allyson K Palmer, Nino Giorgadze, Christina Inman, Nathan Gasek, Ming Xu, Kurt O Johnson, Tamar Pirtskhalava, Selim Chaib, Larissa P G Langhi Prata, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G Tullius, Saranya P Wyles, Rambabu Majji, Hari Krishna Yalamanchili, David B Allison, Tamar Tchkonia, James L Kirkland.

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16 INK4a , p21 CIP1 , senescence-associated β-galactosidase (SAβgal), γH2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as "senosensitizers"), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

DOI: https://doi.org/10.1101/2025.08.27.672709
Curr Opin Clin Nutr Metab Care. 2025 Sep 04.

Anabolic and anticatabolic actions of ketone bodies on skeletal muscle: potential relevance in the management of skeletal muscle wasting.

Tyler A Churchward-Venne.

   PURPOSE OF REVIEW: Skeletal muscle loss is a hallmark of aging, disease, and physical inactivity, with few effective treatments. Ketone bodies are lipid-derived molecules whose endogenous production is substantially amplified under conditions characterized by carbohydrate deprivation (e.g. fasting, a ketogenic diet). Orally ingested ketone supplements are now available that can rapidly induce a pronounced state of ketosis lasting hours without dietary carbohydrate restriction. Historically, ketone bodies have been hypothesized to spare muscle protein during starvation. Recently, their potential anabolic and anticatabolic effects on skeletal muscle have garnered renewed research and clinical interest. This review examines emerging evidence on ketone body administration and its influence on skeletal muscle protein turnover and related signaling, with consideration for therapeutic application in muscle wasting and rehabilitation.
RECENT FINDINGS: Oral ketone supplementation has been shown to enhance postprandial muscle protein synthesis (MPS) in healthy young males. Under inflammatory catabolic conditions, ketone bodies may also promote a favorable net protein balance via suppression of muscle protein breakdown (MPB).
SUMMARY: Ketone body administration may attenuate MPB and stimulate MPS, suggesting potential utility in counteracting muscle wasting. However, further studies are needed to elucidate underlying mechanisms and assess long-term effects on muscle mass and function in clinical settings.

Keywords:  beta-hydroxybutyrate; ketone bodies; ketone monoester; muscle protein breakdown; muscle protein synthesis

DOI:  https://doi.org/10.1097/MCO.0000000000001164
Nat Aging. 2025 Aug 28.

Unlocking longevity through the comparative biology of aging.

Cheyenne Rechsteiner, Francesco Morandini, Sei Joong Kim, Andrei Seluanov, Vera Gorbunova.

The comparative biology of aging leverages the remarkable diversity in aging rates and lifespans across species to uncover naturally evolved adaptations that promote longevity, disease resistance and injury resilience. The beauty of comparative biology is that it discovers adaptations that evolved outside of the protected laboratory environment, shaped by natural selection under real-world pressures. In this Review, we outline key approaches in comparative biology of aging studies, including the study of public mechanisms, which are shared between species, and private mechanisms, which are species-specific. Additionally, we present insights gained through high-throughput omics technologies-including genomics, transcriptomics, epigenomics, proteomics and metabolomics-and illustrate how these findings advance our understanding of how to ameliorate the hallmarks of aging, enhance cancer resistance and improve regeneration, with a focus on mammals. Finally, we offer practical guidance for designing and interpreting comparative studies aimed at understanding and translating longevity mechanisms.

DOI: https://doi.org/10.1038/s43587-025-00945-8