bims-cesemi 2025-05-11 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–05–11
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.
The context-dependent effect of cellular senescence: From embryogenesis and wound healing to aging.
Mitochondria regulate inositol triphosphate-mediated Ca2+ release triggered by voltage-dependent Ca2+ entry in resistance arteries.
The PARP inhibitor olaparib promotes senescence in murine macrophages.
Therapy-induced senescence of glioblastoma cells is determined by the p21CIP1-CDK1/2 axis and does not require activation of DREAM.
KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.
Ion channel expression and function in glioblastoma multiforme (GBM): pathophysiological mechanisms and therapeutic potential.
Functional mitochondrial respiration is essential for glioblastoma tumour growth.
Accelerated Aging in Cancer and Cancer Treatment: Current Status of Biomarkers.

EMBO J. 2025 May 09.

Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis.

Furkan E Oflaz, Alexander I Bondarenko, Michael Trenker, Markus Waldeck-Weiermair, Benjamin Gottschalk, Eva Bernhart, Zhanat Koshenov, Snježana Radulović, Rene Rost, Martin Hirtl, Johannes Pilic, Aditya Karunanithi Nivedita, Adlet Sagintayev, Gerd Leitinger, Bent Brachvogel, Susanne Summerauer, Varda Shoshan-Barmatz, Roland Malli, Wolfgang F Graier.

  Annexin A5 (AnxA5) is a Ca2+-dependent phospholipid-binding protein associated with the regulation of intracellular Ca2+ homeostasis. However, the precise role of AnxA5 in controlling mitochondrial Ca2+ signaling remains elusive. Here, we introduce a novel function of AnxA5 in regulating mitochondrial Ca2+ signaling. Our investigation revealed that AnxA5 localizes at and in the mitochondria and orchestrates intermembrane space Ca2+ signaling upon high Ca2+ elevations induced by ER Ca2+ release. Proximity ligation assays and co-immunoprecipitation revealed a close association but no direct contact of AnxA5 with the voltage-dependent anion channel (VDAC1) in the outer mitochondrial membrane (OMM). In single-cell mitochondrial Ca2+ measurements and electrophysiological recordings, AnxA5 was found to enhance Ca2+ flux through the OMM by promoting the Ca2+-permeable state of VDAC1. By modulating intermembrane space Ca2+ signaling, AnxA5 shapes mitochondrial ultrastructure and influences the dynamicity of the mitochondrial Ca2+ uniporter. Furthermore, by controlling VDAC1's oligomeric state, AnxA5 is protective against cisplatin and selenite-induced apoptotic cell death. Our study uncovers AnxA5 as an integral regulator of VDAC1 in physiological and pathological conditions.

Keywords:  Annexin-A5; Apoptotic Cell Death; Intermembrane Space Ca2⁺ Signaling; VDAC1 Ca2+ Permeability

DOI:  https://doi.org/10.1038/s44318-025-00454-9
Ageing Res Rev. 2025 May 01. pii: S1568-1637(25)00106-0. [Epub ahead of print]109 102760

The context-dependent effect of cellular senescence: From embryogenesis and wound healing to aging.

Rupa Lavarti, Tatiana Alvarez-Diaz, Kyarangelie Marti, Parmita Kar, Raghavan Pillai Raju.

  Aging is characterized by a steady loss of physiological integrity, leading to impaired function and increased vulnerability to death. Cell senescence is a biological process that progresses with aging and is believed to be a key driver of age-related diseases. Senescence, a hallmark of aging, also demonstrates its beneficial physiological aspects as an anti-cancer, pro-regenerative, homeostatic, and developmental mechanism. A transitory response in which the senescent cells are quickly formed and cleared may promote tissue regeneration and organismal fitness. At the same time, senescence-related secretory phenotypes associated with extended senescence can have devastating effects. The fact that the interaction between senescent cells and their surroundings is very context-dependent may also help to explain this seemingly opposing pleiotropic function. Further, mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. This review summarizes the mechanism of cellular senescence and the significance of acute senescence. We concisely introduced the context-dependent role of senescent cells and SASP, aspects of mitochondrial biology altered in the senescent cells, and their impact on the senescent phenotype. Finally, we conclude with recent therapeutic advancements targeting cellular senescence, focusing on acute injuries and age-associated diseases. Collectively, these insights provide a future roadmap for the role of senescence in organismal fitness and life span extension.

Keywords:  Acute injury; Aging; Chronic injury; Senescence; Senolytics; Wound healing

DOI:  https://doi.org/10.1016/j.arr.2025.102760
J Physiol. 2025 May 05.

Mitochondria regulate inositol triphosphate-mediated Ca2+ release triggered by voltage-dependent Ca2+ entry in resistance arteries.

Xun Zhang, Charlotte Buckley, Matthew D Lee, Susan Chalmers, Calum Wilson, John G McCarron.

  An increase in cytoplasmic Ca2+ concentration activates multiple cellular activities, including cell division, metabolism, growth, contraction and death. In smooth muscle Ca2+ entry via voltage-dependent Ca2+ channels leads to a relatively uniform increase in cytoplasmic Ca2+ levels that facilitates co-ordinated contraction throughout the cell. However certain functions triggered by voltage-dependent Ca2+ channels require periodic, pulsatile Ca2+ changes. The mechanism by which Ca2+ entry through voltage-dependent channels supports both co-ordinated contraction and distinct cellular responses driven by pulsatile Ca2+ changes is unclear. Here in intact resistance arteries we show that Ca2+ entry via voltage-dependent Ca2+ channels evokes Ca2+ release via inositol triphosphate receptors (IP3Rs), generating repetitive Ca2+ oscillations and waves. We also show that mitochondria play a vital role in regulating Ca2+ signals evoked by voltage-dependent Ca2+ entry by selectively modulating Ca2+ release via IP3Rs. Depolarizing the mitochondrial membrane inhibits Ca2+ release from internal stores, reducing the overall signal-generated Ca2+ influx without altering the signal resulting from voltage-dependent Ca2+ entry. Notably neither Ca2+ entry via voltage-dependent Ca2+ channels nor Ca2+ release via IP3Rs alters mitochondrial location or mitochondrial membrane potential in intact smooth muscle cells. Collectively these results demonstrate that activation of voltage-dependent Ca2+ channels drives Ca2+ entry, which subsequently triggers Ca2+ release from the internal store in smooth muscle cells. Mitochondria selectively regulate this process by modulating IP3R-mediated amplification of Ca2+ signals, ensuring that different cellular responses are precisely controlled. KEY POINTS: In smooth muscle Ca2⁺ entry via voltage-dependent channels produces a uniform Ca2⁺ increase, enabling co-ordinated contraction in each cell. Certain functions, however, require large, pulsatile Ca2⁺ changes rather than a uniform increase. Using advanced imaging in intact arteries, we discovered that voltage-dependent Ca2⁺ entry triggers internal store Ca2⁺ release via IP₃ receptors, generating repetitive Ca2⁺ oscillations and waves. Mitochondria selectively modulate these signals by regulating only IP₃ receptor-mediated release; neither mitochondrial location nor membrane potential is altered by either type of Ca2+ signal. These findings demonstrate how voltage-dependent Ca2⁺ entry supports both co-ordinated contraction and pulsatile Ca2⁺-driven biological responses.

Keywords:  inositol triphosphate receptors; mitochondria; smooth muscle cells; voltage‐dependent Ca2+ channels

DOI:  https://doi.org/10.1113/JP288022
Geroscience. 2025 May 06.

The PARP inhibitor olaparib promotes senescence in murine macrophages.

Anna Kieronska-Rudek, Karim Zuhra, Kelly Ascenção, Stefan Chlopicki, Csaba Szabo.

  Cellular senescence is a multifaceted process involving cell cycle arrest, telomere shortening, and the accumulation of DNA damage associated with aging and cellular stress. It is marked by persistent cell cycle arrest and DNA damage accumulation, and plays an increasingly recognized role in age-related diseases and cancer therapy. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for use in ovarian cancer treatment. We hypothesized that olaparib may influence senescence by inhibiting DNA damage repair, and investigated its effects on non-senescent and replicatively senescent murine macrophages (RAW 264.7 cells). Senescent cells exhibited elevated baseline levels of PARP1 expression, PARylation, and DNA damage relative to non-senescent control cells. Olaparib amplified these differences by upregulating senescence markers (SA-β-gal and p21), inhibiting proliferation, and exacerbating DNA damage. Many of its effects were more pronounced in senescent cells. At higher concentrations (10-30 µM), olaparib induced significant cytotoxicity through mixed apoptotic and necrotic mechanisms, with senescent cells exhibiting a predominantly necrotic response. Interestingly, both mitochondrial activity and cellular bioenergetics were elevated in senescent cells at baseline, and were more severely impaired by olaparib compared to non-senescent control cells. These findings underscore olaparib's enhanced cytotoxic and pro-senescent effects in senescent immune cells and suggest potential implications for its use in elderly cancer patients with an increased burden of senescent cells.

Keywords:  Aging; Macrophages; Olaparib; PARPs; Senescence

DOI:  https://doi.org/10.1007/s11357-025-01679-6
Cell Death Dis. 2025 May 03. 16(1): 357

Therapy-induced senescence of glioblastoma cells is determined by the p21CIP1-CDK1/2 axis and does not require activation of DREAM.

Christian Schwarzenbach, Justus Rinke, Juliana B Vilar, Jason Sallbach, Larissa Tatsch, Ariane Schmidt, Anna Schöneis, Birgit Rasenberger, Bernd Kaina, Maja T Tomicic, Markus Christmann.

Therapy-induced senescence (TIS) is a major challenge in cancer therapy as senescent cancer cells provoke local and systemic inflammation and might be the cause of recurrences. Elucidation of pathways leading to TIS is of utmost importance for establishing strategies to counteract this. Previously we have shown that temozolomide (TMZ), an alkylating drug used forefront in glioma therapy, causes majorly cellular senescence, which is triggered by the primary damage O6-methylguanine, activating the mismatch repair dependent ATR/ATM-CHK1/CHK2-p53 damage response pathway. The downstream pathways leading to TIS remained to be explored. Here, we show that TMZ-induced TIS in glioma cells does not require activation of the DREAM complex, but is bound on a G2-specific response. We show that the CDK inhibitor p21CIP1 does not interact with CDK4, but with CDK1 and CDK2 causing abrogation of the B-Myb and FOXM1-signaling pathway and subsequently arrest of cells in the G2-phase. The induced G2-arrest is incomplete as DNA synthesis can be resumed leading to endoreduplications. This process, which is inhibited by the CDK4-blocking drug palbociclib, is preceded by reactivation of the G1/S-specific E2F1-signaling pathway due to lack of functional DREAM activation. These findings provide an explanation for the polyploidization and giant cell phenotype of anticancer drug-induced senescent cells. Incomplete DREAM activation may also explain the observation that downregulation of DNA repair is a transient phenomenon, which goes along with the entrance of cells into the senescent state.

DOI: https://doi.org/10.1038/s41419-025-07651-8
Nat Commun. 2025 May 09. 16(1): 4327

KAT5 regulates neurodevelopmental states associated with G0-like populations in glioblastoma.

Anca B Mihalas, Sonali Arora, Samantha A O'Connor, Heather M Feldman, Christine E Cucinotta, Kelly Mitchell, John Bassett, Dayoung Kim, Kang Jin, Pia Hoellerbauer, Jennifer Delegard, Melissa Ling, Wesley Jenkins, Megan Kufeld, Philip Corrin, Lucas Carter, Toshio Tsukiyama, Bruce Aronow, Christopher L Plaisier, Anoop P Patel, Patrick J Paddison.

Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.

DOI: https://doi.org/10.1038/s41467-025-59503-w
Biochim Biophys Acta Mol Cell Res. 2025 May 05. pii: S0167-4889(25)00087-4. [Epub ahead of print]1872(6): 119982

Ion channel expression and function in glioblastoma multiforme (GBM): pathophysiological mechanisms and therapeutic potential.

Gauri C Kulkarni, Rayna Saha, Christian J Peters.

  Glioblastoma Multiforme (GBM) is a highly malignant and diffusely invasive WHO Grade IV brain tumor arising from glial and neural stem cells. GBM is characterized by rapid proliferation and migration, aggressive invasion of local brain parenchyma, a hypoxic microenvironment, resistance to apoptosis and high vascular remodeling and angiogenesis. These hallmarks contribute to a near universal tumor recurrence after treatment or resection and poor patient prognosis. Ion channels, a superfamily of proteins responsible for permitting ion flux across otherwise impermeant membranes, show extensive remodeling in GBM with aberrant function mechanistically linked to manipulation of each of these hallmarks. In this review, we will discuss the known links between ion channel expression and activity and cellular processes that are enhanced or perturbed during GBM formation or progression. We will also discuss the extent to which basic or translational findings on ion channels in GBM samples or cell lines have shown preclinical promise towards the development of improved therapeutics against GBMs.

Keywords:  Calcium signaling; Glioblastoma multiforme; Ion channels; Mechanisms of proliferation and migration

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119982
Oncogene. 2025 May 05.

Functional mitochondrial respiration is essential for glioblastoma tumour growth.

Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil.

Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

DOI: https://doi.org/10.1038/s41388-025-03429-6
Cancer Med. 2025 May;14(9): e70929

Accelerated Aging in Cancer and Cancer Treatment: Current Status of Biomarkers.

Soniya Abraham, Jay Parekh, Seohyuk Lee, Humayra Afrin, Mariya Rozenblit, Kim R M Blenman, Rachel J Perry, Leah M Ferrucci, Jessica Liu, Melinda L Irwin, Maryam Lustberg.

   BACKGROUND: Aging in humans is a heterogeneous process influenced by both biological and chronological factors. Biological age reflects an individual's physiological reserve and functional status. Increasing evidence suggests that cancer and its therapies accelerate biological aging. Many biomarkers have been evaluated to assess the biological age of patients with cancer. These biomarkers are emerging as potential tools to predict cancer-related toxicity and an individual's functional capacity as well as to individualize treatment.
METHODS: This review summarizes the current literature on aging biomarkers in cancer patients, with a focus on markers of cellular senescence and epigenetic modification. We evaluate the existing evidence supporting their use as predictors of toxicity in patients undergoing chemotherapy and radiation therapy.
RESULTS: Biomarkers such as interleukin-6 (IL-6), leukocyte telomere length (LTL), and DNA methylation age show potential for assessing biological age, frailty, and functional reserve. The expression of p16INK4A has demonstrated promise in predicting therapy-induced toxicity and making treating decisions. However, additional confirmatory studies are necessary to further validate these biomarkers before they can be utilized as decision aids.
CONCLUSION: Aging biomarkers hold promise for individualizing cancer therapy and predicting treatment-related toxicity. However, further studies are essential to validate their reliability and support their integration into clinical practice.

Keywords:  accelerated aging; biomarkers of aging; cancer therapy toxicity; cellular senescence

DOI:  https://doi.org/10.1002/cam4.70929