bims-cesemi 2026-11-01 papers

Issue of 2026–11–01
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Nat Cardiovasc Res. 2026 Oct 27.

Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.

Joshua L Axelrod, Zuzana Nichtová, Timothy Schneider, Jaehoon Lee, Ryan Pekson, Dongze Qin, Madeeha Ghazi, Vinay Kumar, Victoria Margulets, Lorrie A Kirshenbaum, Gaetano Santulli, György Csordás, John W Calvert, Richard N Kitsis.

Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca2+ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca2+ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca2+ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca2+ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.

DOI: https://doi.org/10.1038/s44161-026-00903-6

Traffic. 2026 Dec;pii: e70057. [Epub ahead of print]27(4):

TMEM55B Maintains Lysosomal Homeostasis and Promotes ER-Lysosome Calcium Signaling.

Nagi Mukae, Honoka Maki, Michiko Shirane.

At membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endolysosomal compartments, the Protrudin-PDZD8 complex promotes the maturation of endosomes into lysosomes, a process accompanied by acidification. Endosomal maturation is closely associated with both lysosomal acidification and calcium signaling; however, the molecular mechanisms linking the Protrudin-PDZD8 complex to these processes remain unclear. Here, we identified TMEM55B, a lysosome-localized protein, as a binding partner of the Protrudin-PDZD8 complex. TMEM55B has been reported to interact with the v-ATPase complex, suggesting a role in lysosomal function. Suppression of TMEM55B expression reduced the fluorescence of a lysosomal acidification probe, suggesting impaired lysosomal acidification. In addition, TMEM55B depletion attenuated lysosomal Ca2+ release and reuptake and reduced ATP-induced Ca2+ responses in the ER. These findings suggest impaired calcium-induced calcium release (CICR) at ER-lysosome MCSs. By contrast, mitochondrial Ca2+ dynamics were unaffected. Together, these results identify TMEM55B as a factor involved in maintaining lysosomal homeostasis and regulating calcium dynamics. Our findings suggest that TMEM55B cooperates with the Protrudin-PDZD8 complex to contribute to the regulation of lysosomal function at ER-lysosome MCSs.

Keywords: PDZD8; TMEM55B; calcium signaling; lysosome; membrane contact site

DOI: https://doi.org/10.1111/tra.70057

Neuro Oncol. 2026 Oct 29. pii: noag270. [Epub ahead of print]

Standard treatment against paediatric BRAF-V600E glioma promotes senescence and sensitizes tumours to BCL-xL inhibition.

BACKGROUND: Chemo-, radio-, and targeted therapies can induce a stable growth arrest known as therapy-induced senescence (TIS), which may be therapeutically exploited using senolytic compounds that selectively eliminate senescent cells. Children with BRAF-V600E-driven brain tumours are commonly treated with low-dose chemotherapies and MAPK inhibitors, alone or in combination, often with good initial responses. However, a majority of patients experiences tumour regrowth following treatment withdrawal. Here, we investigate the contribution of TIS to treatment response and relapse, and assess the therapeutic potential of senolytics in preclinical models of paediatric BRAF-V600E glioma.
METHODS: Preclinical models of paediatric low-grade glioma were analysed in vitro or following orthotopic transplantation into mice and treated with Dabrafenib, Trametinib, Tovorafenib or Vinblastine. Senescence was assessed using molecular and cytological markers. Sensitivity to senolytic compounds was evaluated using in vitro dose-response assays and in vivo treatment studies.
RESULTS: Trametinib induced a robust senescent phenotype in BT-40 tumours in vivo, characterised by activation of a senescence-associated secretory phenotype and expansion of IBA-1-positive myeloid cells. In vitro, senescence was induced in BT-40 cells following treatment with MAPK inhibitors and Vinblastine, and was similarly observed in H9-derived human neural stem cells expressing BRAF-V600E. Navitoclax was identified as a potent senolytic against senescent BT-40 cells, primarily through inhibition of the anti-apoptotic protein BCL-xL. In vivo, combined Trametinib and Navitoclax treatment ablated senescent tumour cells, significantly reduced tumour regrowth after treatment withdrawal, and improved survival.
CONCLUSIONS: These findings demonstrate that Navitoclax enhances Trametinib's anti-tumour efficacy and limits tumour relapse following treatment cessation.

Keywords: BRAF-V600E driven glioma; BT-40; MAPK inhibitors; Navitoclax; senescence

DOI: https://doi.org/10.1093/neuonc/noag270

J Cell Biol. 2026 Dec 07. pii: e202606052. [Epub ahead of print]225(12):

Lysosomal acidification through membrane contacts with mitochondria.

Zhiqi Tian, Yujie Sun, Jiajie Diao.

Recent work from two independent studies has uncovered mitochondria as a previously unrecognized proton source driving lysosomal acidification. In this Viewpoint, we summarize these findings, examine the associated proteins and functional mechanisms, and discuss their relevance to disease.

DOI: https://doi.org/10.1083/jcb.202606052

Curr Issues Mol Biol. 2026 Oct 08. pii: 1041. [Epub ahead of print]48(10):

A Novel Combination of Galega officinalis Extract, Hippophae rhamnoides Fruit Oil and Resveratrol Attenuates Bleomycin-Induced Senescence Markers in Human Dermal Fibroblasts and Ex Vivo Hair Follicles.

Ana Lobo Aldezabal, Irene Cáceres Estévez, Marta Escobar Gómez Rodulfo, Sandra Fernández-Martos, María Calvo-Sánchez, Luisa Haya Rodríguez, Ana López Sánchez, Luis Nieto Botella, Manuel Asín, José Manuel Carbajo, Jesús Espada Regalado.

Senescence is an adaptive state activated in cells when external or internal damage exceeds the homeostatic capacity of background resilience mechanisms. It is characterized by a stable cell-cycle arrest, chromatin reorganization, and the acquisition of a senescence-associated secretory phenotype (SASP). While senescence can have beneficial roles in tissue repair, the accumulation of senescent cells contributes to inflammation, stem cell dysfunction, and tissue degeneration. In this context, the identification of compounds able to modulate the threshold between tissue resilience and cellular senescence, by partially eliminating senescent cells to preserve tissue function, is a major target of biomedical research. Here, we present a novel ingredient consisting of a combination of Galega officinalis extract, Hippophae rhamnoides fruit oil, and resveratrol (Metforhair®, MFH). We report that MFH partially reduces senescence-associated features, using human primary dermal fibroblasts as an experimental validation model. Consequently, we used ex vivo cultures of human hair follicles to evaluate the ability of MFH to attenuate senescence markers. Our results support the use of MFH as a hair follicle therapy, which modestly reduces hallmarks of cellular senescence.

Keywords: Galega officinalis; Hippophae rhamnoides; hair follicle; resilience; resveratrol; senescence

DOI: https://doi.org/10.3390/cimb48101041

Int J Radiat Oncol Biol Phys. 2026 Oct 24. pii: S0360-3016(26)04391-9. [Epub ahead of print]

A senescence-driven fibroblast-macrophage feed-forward circuit promotes radiation induced cutaneous fibrosis.

Eun Joo Chung, Santwana Kc, Seokjoo Kwon, Ayla White, Joon-Yong Chung, Youngjoo Jung, Heesu Ahn, Hong Zhang, Edmund Cauley, Deborah E Citrin.

PURPOSE: Therapeutic radiation for superficial tumors may cause cutaneous fibrosis, a late side effect with limited treatment options. Here, we investigated the underlying mechanisms driving radiation-induced cutaneous fibrosis.
METHODS AND MATERIALS: C3H/HeN mice received 35 Gy unilateral hind limb irradiation. Cutaneous tissues from irradiated and contralateral unirradiated legs were analyzed by spatial whole transcriptome profiling using the GeoMx Digital Spatial Profiler platform. Beginning at 5 weeks after irradiation, mice received the senolytic agent ABT-263 (50 mg/kg/day) or vehicle (n ≥ 10/group) by oral gavage (5 consecutive days followed by 2-week rest for 3 cycles). Hind limb contracture was assessed at 150 days after irradiation. Senescence and macrophage markers were evaluated by immunohistochemistry and quantitative PCR. Cellular senescence and senescence-associated secretory phenotype (SASP) factors were evaluated in irradiated fibroblasts and their culture media using senescence-associated β-galactosidase activity assays and multiplex immunoassays. The senolytic activity of ABT-263 in irradiated primary fibroblasts and effects of ABT-263 on primary macrophage cultures were evaluated in vitro.
RESULTS: Spatial whole-transcriptomic analysis of irradiated murine dermis identified expression patterns consistent with macrophage activation, extracellular matrix remodeling, and a senescence-associated secretory phenotype (SASP)-rich environment. In vitro studies identified that the irradiated fibroblast-derived SASP induced a senescent phenotype in unirradiated fibroblasts and macrophages. SASP-induced senescent-like macrophages acquired a CD206+ profibrotic phenotype and in concert with activated fibroblasts, initiated a feed-forward loop amplifying IL-6 and collagen production. SASP exposure increased expression of Bcl-2 family proteins in macrophages and fibroblasts, rendering both populations susceptible to clearance by the senolytic agent ABT-263. In vivo, ABT-263 effectively mitigated radiation-induced dermal fibrosis, depleted senescent fibroblasts and CD206⁺ macrophages, and reduced IL-6 expression CONCLUSION: Our findings identify senescence-driven reciprocal macrophage-fibroblast interactions as key mediators of cutaneous fibrosis and demonstrate the therapeutic potential of senolytic interventions for treating late radiation-induced skin injury.

Keywords: cutaneous fibrosis; macrophages; radiation therapy; senolytic agent

DOI: https://doi.org/10.1016/j.ijrobp.2026.10.013