bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–04–13
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. TMEM65 joins the mitochondrial Ca2+ club.
  2. Cells are swapping their mitochondria. What does this mean for our health?
  3. TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
  4. Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
  5. Aging-associated mitochondrial decline accelerates skin aging and obesity.
  6. Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
  7. Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.
  8. Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state.
  9. Biophysical characterization of anion channels in Mitochondrion-Endoplasmic-Reticulum Contact sites (MERCs).
  1. Nat Metab. 2025 Apr 08.
    TMEM65 joins the mitochondrial Ca2+ club.
    Yasemin Sancak.
      
    DOI:  https://doi.org/10.1038/s42255-025-01271-4
  2. Nature. 2025 Apr;640(8058): 302-304
    Cells are swapping their mitochondria. What does this mean for our health?
    Gemma Conroy.
      
    Keywords:  Cancer; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-01064-5
  3. Nat Metab. 2025 Apr 08.
    TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
    Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.
      The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01250-9
  4. Cell Death Dis. 2025 Apr 05. 16(1): 253
    Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
    Nikita Markov, Sirina Sabirova, Gulnaz Sharapova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Marcel Egger, Albert Rizvanov, Hans-Uwe Simon.
      The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.
    DOI:  https://doi.org/10.1038/s41419-025-07596-y
  5. J Invest Dermatol. 2025 Apr 08. pii: S0022-202X(25)00395-1. [Epub ahead of print]
    Aging-associated mitochondrial decline accelerates skin aging and obesity.
    Shuji Yamamura, Haruki Horiguchi, Tsuyoshi Kadomatsu, Keishi Miyata, Daisuke Torigoe, Takehisa Suzuki, Michio Sato, Kimi Araki, Akira Suzuki, Satoshi Fukushima, Yuichi Oike.
      Skin tissue, which consists of epidermal, dermal, and hypodermal cells, plays an important role in biological defense and physical appearance. External and internal stresses occurring with aging disrupt skin homeostasis, promoting development of phenotypes associated with aging. While many studies of skin aging focus on the dermis, potential epidermal changes have largely remained uncharacterized. Here, we demonstrate that epidermal cells do not exhibit cellular senescence phenotypes with aging but instead show age-related decreases in mitochondrial number. We also found that mice lacking mitochondrial transcription factor A (TFAM) in epidermal cells exhibit delayed hair regrowth and impaired wound healing by middle age resembling changes seen in skin of aged mice. Furthermore, middle-aged epidermis-specific TFAM-deficient mice exhibited obesity, suggesting that impaired fatty acid metabolism in epidermal cells resulting from mitochondrial decline may lead to obesity. These findings overall suggest that mitochondrial decline occurs as a primary event in epidermal aging, and that anti-aging strategies to enhance activity or number of epidermal mitochondria could antagonize both skin-aging phenotypes and age-related metabolic disease.
    Keywords:  aging; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.jid.2025.03.028
  6. Biochim Biophys Acta Mol Cell Res. 2025 Apr 09. pii: S0167-4889(25)00059-X. [Epub ahead of print] 119954
    Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer.
    Michal Cagalinec, Mohd Adnan, Silvia Borecka, Geert Bultynck, Vinay Choubey, Shira Yanovsky-Dagan, Shlomit Ezer, Daniela Gasperikova, Tamar Harel, Dana Jurkovicova, Allen Kaasik, Jean-Charles Liévens, Tangui Maurice, Marco Peviani, Elodie Marie Richard, Jan Skoda, Martina Skopkova, Pauline Tarot, Robbe Van Gorp, Liga Zvejniece, Benjamin Delprat.
      Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.
    Keywords:  ATAD3A related disorders; Amyotrophic lateral sclerosis; Calcium signaling; Endoplasmic reticulum stress; Familial Parkinson's disease; Harel-Yoon syndrome; Metabolomics; Mitochondria quality control; Mitochondria-associated endoplasmic reticulum membranes; Rare neurodegenerative diseases; Wolfram syndrome; cancer
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119954
  7. Cell. 2025 Apr 04. pii: S0092-8674(25)00282-X. [Epub ahead of print]
    Quiescent cell re-entry is limited by macroautophagy-induced lysosomal damage.
    Andrew Murley, Ann Catherine Popovici, Xiwen Sophie Hu, Anina Lund, Kevin Wickham, Jenni Durieux, Larry Joe, Etai Koronyo, Hanlin Zhang, Naomi R Genuth, Andrew Dillin.
      To maintain tissue homeostasis, many cells reside in a quiescent state until prompted to divide. The reactivation of quiescent cells is perturbed with aging and may underlie declining tissue homeostasis and resiliency. The unfolded protein response regulators IRE-1 and XBP-1 are required for the reactivation of quiescent cells in developmentally L1-arrested C. elegans. Utilizing a forward genetic screen in C. elegans, we discovered that macroautophagy targets protein aggregates to lysosomes in quiescent cells, leading to lysosome damage. Genetic inhibition of macroautophagy and stimulation of lysosomes via the overexpression of HLH-30 (TFEB/TFE3) synergistically reduces lysosome damage. Damaged lysosomes require IRE-1/XBP-1 for their repair following prolonged L1 arrest. Protein aggregates are also targeted to lysosomes by macroautophagy in quiescent cultured mammalian cells and are associated with lysosome damage. Thus, lysosome damage is a hallmark of quiescent cells, and limiting lysosome damage by restraining macroautophagy can stimulate their reactivation.
    Keywords:  aging; endoplasmic reticulum; lysosome; mTOR; macroautophagy; protein aggregates; quiescence
    DOI:  https://doi.org/10.1016/j.cell.2025.03.009
  8. Metabolism. 2025 Apr 04. pii: S0026-0495(25)00128-3. [Epub ahead of print] 156259
    Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state.
    Ji-Won Shin, Dong-Hyun Jang, So Young Kim, Je-Jung Lee, Tae-Hwan Gil, Eunha Shim, Ji Yeon Kim, Hyeon Soo Kim, Michael J Conboy, Irina M Conboy, Christopher D Wiley, Jeon-Soo Shin, Ok Hee Jeon.
       BACKGROUND & PURPOSE: Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence.
    METHODS: We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. Senescence was determined by SA-β-gal & EdU staining, p16INK4a and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.
    RESULTS: Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration.
    CONCLUSION: ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.
    Keywords:  Cellular senescence; Extracellular HMGB1; Paracrine senescence; Redox; SASP
    DOI:  https://doi.org/10.1016/j.metabol.2025.156259
  9. Biophys J. 2025 Apr 04. pii: S0006-3495(25)00214-0. [Epub ahead of print]
    Biophysical characterization of anion channels in Mitochondrion-Endoplasmic-Reticulum Contact sites (MERCs).
    Shridhar Kiran Sanghvi, Denis Gabrilovich, Satish K Raut, Ajay Gopalan, Aryan Singh, Harmeet Rireika Bhachu, Mayukha Dyta, Veronica Loyo-Celis, Jenna Thuma, Devasena Ponnalagu, Jonathan Davis, Shubha Gururaja Rao, Harpreet Singh.
      The mitochondrion-endoplasmic reticulum (ER) contact sites (MERCs, also known as mitochondrial-associated membranes (MAMs)) are specialized regions of the endoplasmic reticulum that are in close proximity to the mitochondrion. These organelle structures play essential roles in a variety of processes, such as calcium signaling, lipid metabolism, renin-angiotensin-aldosterone system control, the unfolded protein response, and autophagy. MERCs are known to actively participate in ion transport between the ER and mitochondria. Although active calcium channels in MERCs have been detected, limited studies have been carried out to identify or characterize functional anion channels. Here, we tested whether functional anion channels are present in MERCs. We isolated MERCs from mouse organs (heart and brain) and reconstituted them in planar bilayers. The single-channel properties were recorded in the presence of various anion channel blockers or antagonists (IAA-94, DIDS, A9C, and NPPB). We corroborated the presence of anion channels targeted by these drugs using immunoblotting and immunocytochemistry. Biochemical analysis and immunocytochemistry corroborate that CLIC4, CLIC3, and VDACs are present in MERCs. Our results indicate that anion channels are active in MERCs, which could play a pertinent role in intracellular organelle communication.
    Keywords:  Mitochondria-Endoplasmic-Reticulum (ER) Contact sites (MERCs); anion channels; cardiomyocytes; electrophysiology; mitochondrial-associated membranes
    DOI:  https://doi.org/10.1016/j.bpj.2025.04.002
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