bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–06–07
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Cancer as a window into mitochondrial biology.
  2. Plasma - Activated Medium Engages Redox Signaling to Activate a VDAC1-TRPML1 Lysosomal-Mitochondrial Ca2+ Death Pathway.
  3. The love and hate relationship between cellular senescence and stemness.
  4. Cellular senescence escape and antiviral response discriminate glioblastoma from lower-grade gliomas.
  5. TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
  6. Deterioration of Liver Fibrosis by ALR Deficiency is associated with reducing MICU1/2 Heterodimerization and Mitochondrial Ca2+ imbalance in Hepatic Stellate Cell.
  7. Europe is ditching US tech - what does this mean for researchers?
  8. Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
  1. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00188-9. [Epub ahead of print]38(6): 1085-1088
    Cancer as a window into mitochondrial biology.
    Thomas MacVicar, Laura C Greaves, Payam A Gammage, Stephen W G Tait, Kelsey H Fisher-Wellman, Gordon Freedman.
      Cancer has revealed that the mitochondrion is not a static organelle but a system of extraordinary plasticity. Here, we introduce fundamental mitochondrial behaviors that have been illuminated by cancer research and propose that further investigation in mitochondrial biology holds promise for oncology and beyond.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.003
  2. Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00848-8. [Epub ahead of print]
    Plasma - Activated Medium Engages Redox Signaling to Activate a VDAC1-TRPML1 Lysosomal-Mitochondrial Ca2+ Death Pathway.
    Pengpeng Huang, Yan Zheng, Chuanzan Zhou, Chengbiao Ding, Qi Zhang, Dechao Feng, Zhengwei Wu.
      Plasma-activated medium (PAM), a redox-active anticancer modality, induces cytotoxicity in multiple tumor models, but the mechanisms underlying PAM-induced tumor cell death remain incompletely understood. Here, using A549 lung cancer cells together with additional tumor models, we identify a lysosome - mitochondria Ca2+ circuit that drives a distinct form of PAM-induced tumor-selective cell death. PAM promotes the coupling of the lysosomal Ca2+ channel TRPML1 to the mitochondrial outer membrane protein VDAC1 at organelle contact sites, leading to lysosomal Ca2+ release, mitochondrial Ca2+ overload, membrane depolarization, cytochrome c release, and cell death. Mechanistically, PAM suppresses mTORC2 - SGK1 signaling, reduces VDAC1 phosphorylation at Ser104, and stabilizes VDAC1 on mitochondria. Accumulated VDAC1 then engages TRPML1 through Lys109 and Arg163 to facilitate pathological Ca2+ transfer. Disrupting this interface, or restoring phosphomimetic control of VDAC1, attenuated mitochondrial Ca2+ overload, improved cell survival, and weakened the antitumor effect of PAM in vivo. Pan-cancer analyses further suggested that although high VDAC1 expression is associated with poor prognosis, it may help stratify tumors more likely to respond to PAM. Together, these findings establish the VDAC1 - TRPML1 axis as a key mechanistic link between PAM-induced redox stress and lysosome - mitochondria Ca2+-dependent tumor cell death, and highlight this pathway as a potential therapeutic target and response biomarker.
    Keywords:  Mitochondria; Mitochondrial calcium overload; Plasma Activated Medium; Ubiquitination; VDAC1-TRPML1 interaction sites; lysosome crosstalk
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.003
  3. Aging (Albany NY). 2026 May 30. 18(1): 656-675
    The love and hate relationship between cellular senescence and stemness.
    Angelos Papaspyropoulos, Giorgos Theocharous, Orestis A Ntintas, Konstantinos Evangelou, Vassilis G Gorgoulis.
      Cellular senescence and stemness represent two biological entities with several opposing properties. However, both senescence and stemness serve to maintain tissue homeostasis, via different mechanisms. In adults, while non-dividing senescent cells represent a major barrier to potentially harmful cell insults, propagating stem cells are responsible for restoring the structure and functionality of damaged tissue. In this review, we highlight distinct cellular settings where an antagonistic relationship between the two states is naturally established. In contrast, major synergy between senescence and stemness is observed primarily in cancer, where inherent senescent cell features may actively promote the emergence of cancer stem cells. As the complex interplay between senescence and stemness may heavily vary between different cell types and physiological contexts, elucidating the nature of the interaction and the potential effects per case, is of considerable clinical importance.
    Keywords:  senescence; stemness
    DOI:  https://doi.org/10.18632/aging.206387
  4. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag122
    Cellular senescence escape and antiviral response discriminate glioblastoma from lower-grade gliomas.
    Dominika Maurencova, Michaela Sadibolova, Monika Zarska, Zuzana Liblova, Josef Novak, Jirina Kroupova, Pavla Vasicova, Jiri Bartek, Zdenek Hodny.
      Background. Cellular senescence is a negative prognostic indicator in glioblastoma (GB). However, the specific cell types exhibiting senescence and the molecular mechanisms by which senescent cells (SCs) contribute to GB pathogenesis remain unknown. Methods. We performed multi-omics integration of publicly available GB patient-derived datasets to identify SCs and their functional impact on GB pathogenesis. We created a transcriptomic definition of SCs to verify their presence in GB datasets. Next, we analyzed transcriptomic profiles of GB and low-grade gliomas to reveal key features of GB aggressiveness. The GB patients' phosphoproteome was analyzed with a focus on key regulators of senescence. To assess chemotherapy-evoked secondary senescence, we performed a proteomic analysis of temozolomide-induced senescence in human GB spheroids. Results. We identified GB-associated SCs in clusters radial glia, endothelial cells, and immature astrocytes localized primarily in the hypoxic zones. Notably, we identified senescence-escape features and tumor antiviral responses as processes distinguishing GB from low-grade gliomas. In GB samples, we detected inhibitory phosphorylation of p21 and p27 proteins and active PI3K signaling, which can lead to senescence escape and belong to the typical manipulation arsenal of herpesviruses. Our proteomic analysis of temozolomide-induced senescent GB cells reveals that primary (pre-radiochemotherapy) and secondary senescence in GB share similar phenotypic features. Pathways associated with GB aggressiveness are upregulated after therapy, which can promote more aggressive behavior of recurrent tumors. Conclusions. Our data indicate that senescence and viral reactivation may fuel GB progression, including recurrence, suggesting that senolytics and antiviral drugs are potential therapeutic avenues.
    Keywords:  antiviral response; cellular senescence; glioblastoma; multi‑omics
    DOI:  https://doi.org/10.1093/noajnl/vdag122
  5. Nat Commun. 2026 Jun 05.
    TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
    Hannah E Ball, Abby C Woods, Yvette C Wong.
      Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
    DOI:  https://doi.org/10.1038/s41467-026-74009-9
  6. Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00855-5. [Epub ahead of print]
    Deterioration of Liver Fibrosis by ALR Deficiency is associated with reducing MICU1/2 Heterodimerization and Mitochondrial Ca2+ imbalance in Hepatic Stellate Cell.
    Ye Li, Ming-Qiang Liu, Jing Wang, Zi-Wei Li, Xin Wang, Yan-Bo Wei, Ning Zhang, Ling-Yue Dong, Wei An.
      Hepatic stellate cells (HSCs) activation is a pivotal event in the pathogenesis of liver fibrosis (LF). Mitochondrial calcium (mCa2+) dyshomeostasis is a known driver for HSCs activation. Although we previously demonstrated that augmenter of liver regeneration (ALR) inhibits HSCs activation potentially through regulation of mitochondrial calcium uniporter (MCU) and prevention of mCa2+ overload, the precise molecular mechanisms remain poorly understood. In this study we revealed that hepatic ALR expression was continuously reduced with LF progression in both patients and mice, which coincided with a loss of MICU1/2 dimerization. Similarly, Alr deletion (Alr-KO) could exacerbate LF progression in mice fed a choline-deficient high-fat diet, subjected to bile duct ligation or developing spontaneous LF. In vitro studies showed that Alr-KO disrupted the dimerization of mitochondrial calcium uptake 1 and 2 (MICU1/2), core regulatory components of MCU complex, deteriorating mCa2+ overload and promoting HSCs activation. Protein-binding assays revealed that the regulation of MICU1/2 dimerization by ALR appeared indirect; instead, it potentially relied on CHCHD4, a member of the mitochondrial disulfide relay system (DRS). Further data analyses demonstrated that ALR interacted with CHCHD4 at cysteine residues C4, C53 and C55 via modulating its redox status. Alr knockdown or mutation of these cysteine residues in CHCHD4 restrained ALR-CHCHD4 interaction, reduced dimerized MICU1/2 levels, and consequently led to mCa2+ overload and HSCs activation. Overall, this study provides mechanistic insights into how ALR attenuates liver fibrosis by promoting MICU1/2 dimerization and maintaining mCa2+ homeostasis in HSCs.
    Keywords:  Augmenter of liver regeneration; CHCHD4; HSCs; Liver fibrosis; mCa(2+)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.010
  7. Nature. 2026 Jun 05.
    Europe is ditching US tech - what does this mean for researchers?
    Diana Kwon.
      
    Keywords:  Politics; Technology
    DOI:  https://doi.org/10.1038/d41586-026-01610-9
  8. bioRxiv. 2026 May 21. pii: 2026.05.19.726308. [Epub ahead of print]
    Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
    Samantha A McLaughlin, Kendall W Knechtel, Zelia M Correa, J William Harbour, Daniel Pelaez.
      Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.
    DOI:  https://doi.org/10.64898/2026.05.19.726308
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