bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–02–02
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst.
  2. The roles of mitochondria in global and local intracellular calcium signalling.
  3. Remodeling of ER Membrane Contact Sites During Cell Division.
  4. You better keep an eye on your contacts.
  5. Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
  6. Epigenetic modification increases skeletal muscle resilience to metabolic stress.
  7. Spatial metabolomics to unravel cellular metabolism.
  8. Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
  9. Phosphorylation of Bok at Ser-8 blocks its ability to suppress IP3R-mediated calcium mobilization.
  10. SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
  11. Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
  12. Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics.
  1. Oncol Res. 2025 ;33(2): 397-406
    MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst.
    Edmund Cheung So, Louis W C Chow, Chin-Min Chuang, Cing Yu Chen, Cheng-Hsun Wu, Lian-Ru Shiao, Ting-Tsz Ou, Kar-Lok Wong, Yuk-Man Leung, Yi-Ping Huang.
       Objectives: Mitochondrial Ca2+ uniporter (MCU) provides a Ca2+ influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca2+ rise stimulates ATP production and cell growth. MCU is highly expressed in various cancer cells including breast cancer cells, thereby increasing the capacity of mitochondrial Ca2+ uptake, ATP production, and cancer cell proliferation. The objective of this study was to examine MCU inhibition as an anti-cancer mechanism.
    Methods: The effects of MCU-i4, a newly developed MCU inhibitor, on cell viability, apoptosis, cytosolic Ca2+, mitochondrial Ca2+ and potential, glycolytic rate, generation of ATP, and reactive oxygen species, were examined in breast cancer BT474 cells.
    Results: MCU-i4 caused apoptotic cell death, and it decreased and increased, respectively, mitochondrial and cytosolic Ca2+ concentration. Inhibition of MCU by MCU-i4 revealed that cytosolic Ca2+ elevation resulted from endoplasmic reticulum (ER) Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RYR). Unexpectedly, MCU-i4 enhanced glycolysis and ATP production; it also triggered a large production of reactive oxygen species (ROS) and mitochondrial membrane potential collapse.
    Conclusion: Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS. It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis. Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.
    Keywords:  BT474 cells; Breast cancer; Cell death; MCU-i4; Mitochondria Ca2+ uniporter (MCU)
    DOI:  https://doi.org/10.32604/or.2024.052743
  2. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  3. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564241309207
    Remodeling of ER Membrane Contact Sites During Cell Division.
    Fang Yu, Khaled Machaca.
      Membrane contact sites (MCS) provide specialized conduits for inter-organelle communications to maintain cellular homeostasis. Most organelles are interconnected, which supports their coordination and function. M-phase (mitosis or meiosis) is associated with dramatic cellular remodeling to support cell division, including the equal distribution of organelles to the two daughter cells. However, the fate of MCS in M-phase is poorly understood. Here we review recent advances arguing for differential remodeling of endoplasmic reticulum (ER) MCS with the plasma membrane (PM, ERPMCS) and the mitochondria (MERCS) during cell division.
    Keywords:  ERPMCS; MERCS; cell division; endoplasmic reticulum; meiosis; membrane contact sites; mitochondrion (mitochondria); mitosis
    DOI:  https://doi.org/10.1177/25152564241309207
  4. Cell Calcium. 2025 Jan 22. pii: S0143-4160(25)00008-9. [Epub ahead of print]126 102999
    You better keep an eye on your contacts.
    Tamas Balla, Gergo Gulyas.
      Membrane contact sites (MCS) are specialized compartments found in all eukaryotic cells that are formed between membranes of different organelles that are in close proximity. MCS have important functions as they are sites of efficient transfer of molecules between neighboring organelles. Two recent articles have used the splitFAST system to mark and follow the dynamics of membrane contact sites and used the method to highlight the importance of MCS between the endoplasmic reticulum (ER) and lipid droplets in metabolic adaptation and MCS between the ER and mitochondria in Ca2+ signal propagation.
    Keywords:  Calcium signaling; Lipid droplets; Lipid transfer; Membrane contact sites; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2025.102999
  5. iScience. 2025 Jan 17. 28(1): 111656
    Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
    Kevin Kiesworo, Thomas Agius, Michael R Macarthur, Martine Lambelet, Arnaud Lyon, Jing Zhang, Guillermo Turiel, Zheng Fan, Sènan d'Almeida, Korkut Uygun, Heidi Yeh, Sébastien Déglise, Katrien de Bock, Sarah J Mitchell, Alejandro Ocampo, Florent Allagnat, Alban Longchamp.
      Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.
    Keywords:  Cellular physiology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111656
  6. Nat Metab. 2025 Jan 27.
    Epigenetic modification increases skeletal muscle resilience to metabolic stress.
      
    DOI:  https://doi.org/10.1038/s42255-024-01211-8
  7. Nat Rev Genet. 2025 Jan 28.
    Spatial metabolomics to unravel cellular metabolism.
    Arafath K Najumudeen, Johan Vande Voorde.
      
    DOI:  https://doi.org/10.1038/s41576-025-00817-2
  8. Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]
    Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
    Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.
    Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism
    DOI:  https://doi.org/10.1016/j.tem.2025.01.003
  9. Cell Commun Signal. 2025 Jan 14. 23(1): 27
    Phosphorylation of Bok at Ser-8 blocks its ability to suppress IP3R-mediated calcium mobilization.
    Caden G Bonzerato, Katherine R Keller, Richard J H Wojcikiewicz.
       BACKGROUND: Bok is a poorly characterized Bcl-2 protein family member with roles yet to be clearly defined. It is clear, however, that Bok binds strongly to inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which govern the mobilization of Ca2+ from the endoplasmic reticulum, a signaling pathway required for many cellular processes. Also known is that Bok has a highly conserved phosphorylation site for cAMP-dependent protein kinase at serine-8 (Ser-8). Whether Bok, or phosphorylated Bok, has any direct impact on the Ca2+ mobilizing function of IP3Rs remains to be established.
    METHODS: Bok Ser-8 phosphorylation was characterized using purified proteins, G-protein coupled receptor agonists that increase cAMP levels in intact cells, mass spectrometry, and immunoreactivity changes. Also, using mammalian cells that exclusively or predominately express IP3R1, to which Bok binds strongly, and a fluorescent Ca2+-sensitive dye or a genetically-encoded Ca2+ sensor, we explored how endogenous and exogenous Bok controls the Ca2+ mobilizing function of IP3R1, and whether Bok phosphorylation at Ser-8, or replacement of Ser-8 with a phosphomimetic amino acid, is regulatory.
    RESULTS: Our results confirm that Ser-8 of Bok is phosphorylated by cAMP-dependent protein kinase, and remarkably that phosphorylation can be detected with Bok specific antibodies. Also, we find that Bok has suppressive effects on IP3R-mediated Ca2+ mobilization in a variety of cell types. Specifically, Bok accelerated the post-maximal decline in G-protein coupled receptor-induced cytosolic Ca2+ concentration, via a mechanism that involves suppression of IP3R-dependent Ca2+ release from the endoplasmic reticulum. These effects were dependent on the Bok-IP3R interaction, as they are only seen with IP3Rs that can bind Bok (e.g., IP3R1). Surprisingly, Bok phosphorylation at Ser-8 weakened the interaction between Bok and IP3R1 and reversed the ability of Bok to suppress IP3R1-mediated Ca2+ mobilization.
    CONCLUSIONS: For the first time, Bok was shown to directly suppress IP3R1 activity, which was reversed by Ser-8 phosphorylation. We hypothesize that this suppression of IP3R1 activity is due to Bok regulation of the conformational changes in IP3R1 that mediate channel opening. This study provides new insights on the role of Bok, its interaction with IP3Rs, and the impact it has on IP3R-mediated Ca2+ mobilization.
    Keywords:  Bcl-2 family proteins; Bok; Calcium signaling; ER; ER calcium leak; GPCR; IP3R; PKA; Phosphorylation
    DOI:  https://doi.org/10.1186/s12964-024-02008-8
  10. Nat Commun. 2025 Jan 30. 16(1): 1181
    SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
    Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.
      Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.
    DOI:  https://doi.org/10.1038/s41467-025-56402-y
  11. J Cell Sci. 2025 Jan 29. pii: jcs.263685. [Epub ahead of print]
    Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
    Jason C Casler, Clare S Harper, Laura L Lackner.
      Cells form multiple, molecularly distinct membrane contact sites (MCSs) between organelles. Despite knowing the molecular identity of several of these complexes, little is known about how MCSs are coordinately regulated in space and time to promote organelle function. Here, we examined two well-characterized mitochondria-ER MCSs - the ER-Mitochondria encounter structure (ERMES) and the mitochondria-ER-cortex anchor (MECA). We report that loss of MECA results in a substantial reduction in the number of ERMES contacts. Rather than reducing ERMES protein levels, loss of MECA results in an increase in the size of ERMES contacts. Using live cell microscopy, we demonstrate that ERMES contacts display several dynamic behaviors, such as de novo formation, fusion, and fission, that are altered in the absence of MECA or by changes in growth conditions. Unexpectedly, we find that the mitochondria-PM tethering, not the mitochondria-ER tethering, function of MECA regulates ERMES contacts. Remarkably, synthetic tethering of mitochondria to the PM in the absence of MECA is sufficient to rescue the distribution of ERMES foci. Overall, our work reveals how one MCS can influence the regulation and function of another.
    Keywords:  Membrane contact sites; Mitochondria; Mitochondrial positioning
    DOI:  https://doi.org/10.1242/jcs.263685
  12. FEBS J. 2025 Jan 27.
    Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics.
    Samael Olascoaga, Mina Konigsberg, Jesús Espinal-Enríquez, Hugo Tovar, Félix Matadamas-Martínez, Jaime Pérez-Villanueva, Norma Edith López-Diazguerrero.
      Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.
    Keywords:  SCAPs; aging; senescence; senolytics; survival networks
    DOI:  https://doi.org/10.1111/febs.17402
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