bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–08–24
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria.
  2. Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury.
  3. Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
  4. When huffing and puffing Ca2+ goes global, breast cancer cells are unmoved.
  5. Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.
  6. The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
  7. Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.
  8. Targeted Elimination of Senescent Cells by ProcyanidinC1 Improves Diabetic Wound Healing and Restores Skin Quality.
  1. Cell Death Dis. 2025 Aug 18. 16(1): 623
    AMPK regulates ARF1 localization to membrane contact sites to facilitate fatty acid transfer between lipid droplets and mitochondria.
    Lupeng Chen, Yue Liu, Junzhi Zhang, Tongxing Song, Jian Wu, Zhuqing Ren.
      Lipid droplet (LD) -mitochondrion contacts play a crucial role in regulating energy metabolism and fatty acid oxidation in skeletal muscle cells. However, the proteins that regulate these interactions remain poorly understood. Here, we demonstrate that the binding between ADP-ribosylation factor 1(ARF1) and perilipin2 (Plin2) regulates LD-mitochondrion contacts under starvation conditions, facilitating the transfer of fatty acids from LDs to mitochondria. In C2C12 cells, starvation increased ARF1's GTP-binding activity and its localization to mitochondria, enhancing ARF1's binding to Plin2 and facilitating fatty acid flow from LDs to mitochondria. In contrast, knockdown of ARF1 reduced LD-mitochondrion interactions and blocked fatty acids transfer. Additionally, ARF1-mediated interactions were regulated by AMPK; inhibiting AMPK activity reduced ARF1 localization to LDs and mitochondria, and blocked LD-mitochondrion interactions. In mice, starvation increased ARF1 expression in muscle tissue and LD-mitochondrion contacts. Conversely, inhibiting ARF1 led to lipid accumulation in muscle tissue. In conclusion, our work suggests that ARF1 is a critical regulator of LD-mitochondrion interactions and plays a significant role in energy metabolism regulation in skeletal muscle.
    DOI:  https://doi.org/10.1038/s41419-025-07957-7
  2. Nat Commun. 2025 Aug 19. 16(1): 7699
    Noncanonical function of Pannexin1 promotes cellular senescence and renal fibrosis post-acute kidney injury.
    Liuwei Huang, Yanting Shen, Xiaoling Pan, Jiaqi Li, Caizhen Li, Lixin Ruan, Sitan He, Lanlan Huang, Kangyi Liu, Xin Zhao, Jian Geng, Jie Guo, Fan Fan Hou, Jun Wang.
      Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), a transition driven by cellular senescence, a state of irreversible cell-cycle arrest. However, the molecular mechanisms promoting this pathological process remain unclear. Here we show that the channel protein Pannexin1 (Panx1) promotes this detrimental senescence and subsequent kidney fibrosis. We found that Panx1 functions in a noncanonical role as a calcium (Ca2+) leak channel within the endoplasmic reticulum (ER), a key intracellular calcium store. This Panx1-mediated leak occurs at contact sites between the ER and mitochondria, leading to mitochondrial calcium overload, dysfunction, and the generation of pro-senescence signals. Genetically deleting Panx1 in male mouse models of AKI attenuates renal senescence and fibrosis. These findings, validated in human kidney tissue, identify ER-resident Panx1 as a critical driver of kidney disease progression and a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-63152-4
  3. iScience. 2025 Sep 19. 28(9): 113233
    Mitochondrial hyper-acetylation induced by an engineered acetyltransferase promotes cellular senescence.
    Tadahiro Shimazu, Ayane Kataoka, Takehiro Suzuki, Naoshi Dohmae, Yoichi Shinkai.
      Protein acetylation plays crucial roles in diverse biological functions, including mitochondrial metabolism. Although SIRT3 catalyzes the removal of acetyl groups in mitochondria, the addition of the acetyl groups is thought to be primarily controlled in an enzyme-independent manner due to the absence of potent acetyltransferases. In this study, we developed an engineered mitochondria-localized acetyltransferase, named engineered mitochondrial acetyltransferase (eMAT). eMAT localized in the mitochondrial matrix and introduced robust global protein lysine acetylation, including 413 proteins with 1,119 target lysine residues. Notably, 74% of the acetylated proteins overlapped with previously known acetylated proteins, indicating that the eMAT-mediated acetylation system is physiologically relevant. Functionally, eMAT negatively regulated mitochondrial energy metabolism, inhibited cell growth, and promoted cellular senescence, suggesting that mitochondrial hyper-acetylation drives metabolic inhibition and cellular senescence. SIRT3 counteracted eMAT-induced acetylation and metabolic inhibition, restored cell growth, and protected cells from senescence, highlighting the contribution of SIRT3 in maintaining energy metabolism and preventing cellular senescence.
    Keywords:  Metabolic flux analysis; Metabolomics; Protein
    DOI:  https://doi.org/10.1016/j.isci.2025.113233
  4. J Cell Biol. 2025 Sep 01. pii: e202507062. [Epub ahead of print]224(9):
    When huffing and puffing Ca2+ goes global, breast cancer cells are unmoved.
    Woo Young Chung, Shmuel Muallem.
      In this issue, Militsin et al. (https://doi.org/10.1083/jcb.202411203) reveal how STIM1 and STIM2-beyond their typical role as ER Ca2+ sensors that activate Orai1-control IP3R-mediated Ca2+ dynamics, thereby regulating breast cancer cell migration and invasion.
    DOI:  https://doi.org/10.1083/jcb.202507062
  5. Cold Spring Harb Perspect Biol. 2025 Aug 18. pii: a041764. [Epub ahead of print]
    Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.
    Evan Courmont, Anna Rita Cantelmo.
      Calcium is essential for cellular homeostasis, orchestrating a vast array of physiological processes through tightly regulated storage, flux, and signaling pathways. Dysregulation of calcium homeostasis disrupts these finely tuned processes, leading to aberrant signaling that contributes to cancer progression. Beyond its role in cellular dysfunction, calcium also regulates the metabolic reprogramming in cancer cells, enabling them to adapt their metabolism to support tumor growth, survival, and resistance. Despite its fundamental role, direct therapeutic targeting of calcium signaling in cancer remains elusive. This review explores the intricate cross talk between calcium signaling and cancer metabolism, dissecting how distinct calcium dynamics drive adaptive oncogenic adaptations. Deciphering this interplay may reveal therapeutic opportunities that leverage calcium-dependent metabolic vulnerabilities in cancer. Given its broad influence, calcium signaling regulation could serve as a multitargeting strategy for anticancer therapy, broadening the range of potential therapeutic interventions.
    DOI:  https://doi.org/10.1101/cshperspect.a041764
  6. bioRxiv. 2025 Aug 12. pii: 2023.12.02.569652. [Epub ahead of print]
    The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
    Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Jeff Danielson, Amal Elwah, Sierra White, Danyang Li, Callen T Wallace, Felicia Lazure, Esther Elishaev, Lauren Borho, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Benjamin G Bitler, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.
      Cellular senescence, characterized by a stable cell cycle arrest, is a well-documented consequence of several widely used chemotherapeutics that has context-dependent roles in cancer. Although senescent cells are non-proliferative, they remain biologically active and secrete a complex and diverse array of factors collectively known as the se-nescence-associated secretome (SAS), which exerts pro-tumorigenic effects. Here, we aimed to mechanistically investigate how the SAS contributes to metastatic dissemination of high grade serous ovarian cancer (HGSOC) using standard-of-care cisplatin as a se-nescence inducer. Our findings demonstrate that the cisplatin-induced SAS enhances the dissemination of HGSOC in vivo without affecting cell proliferation or viability. We found that the SAS facilitates cell detachment, an effect that is mediated by a metabolic com-ponent. Using a metabolically focused CRISPR knockout screen, we identified complex I as the key driver of SAS-mediated cell detachment in bystander cells and validated that inhibition of complex I activity decreases HGSOC dissemination in vivo . Mechanistically, this effect was driven by SAS-mediated inhibition of an NAD + -SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. Excitingly, we found that fructose is the key SAS component upstream of the NAD + -SIRT-SREBP-cholesterol axis mediating increased detachment of bystander cells, and a high fructose diet increases HGSOC dissemination in vivo . These findings reveal that the cisplatin-induced SAS reprograms the metabolic microenvironment in HGSOC, driving cancer cell detachment and promoting metastatic dissemination in a paracrine fashion. They also point to a previously unrecognized pro-tumorigenic effect of the SAS that may contribute to the high recurrence rate of HGSOC patients.
    DOI:  https://doi.org/10.1101/2023.12.02.569652
  7. FEBS J. 2025 Aug 17.
    Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.
    Maria Poles, Raffaella Pacchiana, Chiara Mortali, Barbara Cisterna, Nidula Mullappilly, Adriana Celesia, Federica Danzi, Martina Gaspari, Daniela Cecconi, Massimo Donadelli, Alessandra Fiore.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.
    Keywords:  MYH14; mitochondrial dynamics; mutant p53; pancreatic ductal adenocarcinoma cancer metabolism
    DOI:  https://doi.org/10.1111/febs.70223
  8. Free Radic Biol Med. 2025 Aug 14. pii: S0891-5849(25)00907-4. [Epub ahead of print]
    Targeted Elimination of Senescent Cells by ProcyanidinC1 Improves Diabetic Wound Healing and Restores Skin Quality.
    Ruoyu Shang, Jiacai Yang, Wengang Hu, Jianhong Hu, Yuanyang Tang, Yangping Wang, Xiaorong Zhang, Li Tao, Xiaohong Hu, Xin Cai, Lingfeng Yan, Lei Yang, Zhihui Liu, Yunxia Chen, Yong Huang, Wenjing Yin, Haisheng Li, Yuanlong Ge, Tiantian Yan, Ruikun He, Zhenyu Ju, Gaoxing Luo, Weifeng He.
      For diabetic patients, impaired wound healing is a serious complication, which characterized by prolonged inflammation, wound granulation tissue formation and impaired re-epithelialization. Accumulating evidence shows that senescent cells play a crucial role in the pathomechanism of diabetic wounds. In this study, we systematically evaluated the role of senescent cells in diabetic wound healing through diabetic mice (DM mice) model (including streptozotocin-induced type I DM mice model and db/db (type II DM) mice model, and actively assessed the therapeutic potential of ProcyanidinC1 (PCC1), the novel senolytic compound. We demonstrated that diabetic mice accumulated a significant number of senescent cells, primarily fibroblasts, in their normal skin and wound tissues. Local application of PCC1 selectively eliminated these senescent cells, leading to improved wound healing outcomes. By modulating the NF-κB signaling axis, PCC1 administration effectively downregulated senescence-associated secretory phenotype components, thereby ameliorating immune dysregulation in diabetic wounds. This therapeutic intervention concurrently revitalized the functional capacity of dermal fibroblasts and vascular endothelial cells, while stimulating coordinated matrix deposition and architectural remodeling of the extracellular compartment. Furthermore, PCC1 treatment enhanced epidermal barrier function after healing, a crucial aspect of wound repair which is often impaired in diabetes. And we also found that PCC1 would improve wound healing at type II diabetic mouse. Collectively, our findings elucidate the complex detrimental roles of senescent cells in diabetic wound repair and establish PCC1-mediated senolytic clearance as a promising therapeutic intervention.
    Keywords:  Cellular senescence; Diabetic wound healing; Extracellular matrix remodeling; PCC1; Senolytic therapy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.028
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