bims-miptne 2026-09-20 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–09–20
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.
Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.
Ubiquitin receptor-mediated, ubiquitin-independent targeted protein degradation via 26S proteasomes.
Glycolysis and T cell-associated gene signature predicts prognosis and therapeutic responses in pancreatic cancer.
Role of cardiac ion pumps, channels, and exchangers on regulation of mitochondrial bioenergetics.
Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
A chromatin-informed transcriptional regulatory framework to stratify patients and guide therapy selection in triple-negative breast cancer.
Cysteine excess triggers a mitochondrial iron-dependent cell death.
A permeable protein nanocage enables facile cargo loading and cytosolic protein delivery.

Cell Death Differ. 2026 Sep 15.

ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.

Elena Frigo, Manuela Santalla, Michele Brischigliaro, Federica Boscolo Nata, Ludovica Tommasin, Michela Rossini, Denis Komarov, Stefania Ferro, Diana Pendin, Oriano Marin, Rodolfo Costa, Michela Carraro, Paolo Bernardi.

Beyond its roles in ATP production and shaping cristae architecture, mitochondrial ATP synthase has been implicated in generating the permeability transition pore (PTP), a Ca2+-activated, high-conductance channel that leads to matrix swelling and cell death in mammalian cells. In Drosophila melanogaster, the PTP homolog rather forms a selective Ca2+-induced Ca2+-release (CICR) channel whose physiological relevance at the organism level remains poorly understood. Here, we down-regulated Drosophila subunits e and g, which are essential for PTP formation in yeast and mammalian cells. Ubiquitous down-regulation of either subunit caused larval developmental arrest, whereas tissue-specific suppression in muscle or neurons led to severe locomotor impairment. Dimerization was markedly reduced, altering mitochondrial ultrastructure while leaving respiratory capacity largely preserved. Strikingly, mitochondria from both knockdown animals accumulated larger Ca2+ loads, consistent with an impaired CICR. This was accompanied by near-complete loss of ecdysone, the Ca2+-dependent master hormone of metamorphosis. Neuron-specific knockdown flies displayed defective mitochondrial Ca2+ efflux and altered synaptic organization at the neuromuscular junction. Altogether, our findings establish that ATP synthase functions as a CICR channel controlling Ca2+ homeostasis, endocrine signaling and development in Drosophila.

DOI: https://doi.org/10.1038/s41418-026-01869-5
Mol Biol Rep. 2026 Sep 18. pii: 1595. [Epub ahead of print]53(1):

Mitochondrial metabolite transporters at the crossroads of metabolic reprogramming, epigenetic regulation and therapeutic vulnerabilities in colorectal cancer.

Kaviya S, Sumathy Arockiasamy, K Satish Srinivas, Sundersingh Shirley.

  Metabolic reprogramming is a defining hallmark of CRC. The Warburg effect is the principal metabolic feature of CRC cells, wherein glucose is preferentially catabolized into lactate to sustain accelerated proliferation. In parallel, CRC cells exhibit strong glutamine reliance to replenish tricarboxylic acid (TCA) cycle intermediates required for adenosine triphosphate (ATP) production, lipid biosynthesis and redox homeostasis. Consequently, mitochondria play a central role in supporting the augmented biosynthetic and energetic demands beyond basal energy homeostasis. In this regard, the mitochondrial pyruvate carrier (MPC), mitochondrial citrate carrier (CIC) and the mitochondrial glutamine carrier (SLC1A5_var) located in the inner mitochondrial membrane, are emerging areas of investigation in CRC metabolism. MPC is frequently lost or downregulated in CRC, whereas CIC was found to be upregulated and promote CRC growth and survival. In contrast, SLC1A5_var has been reported to exhibit elevated expression in colon cancer cells. Recent evidence indicates that its inhibition reduces CRC cell viability; however, its specific role in CRC progression remains to be elucidated. Notably, these transporters may influence the metabolic-epigenetic landscape of CRC through metabolite-dependent regulation of chromatin and transcriptional processes. This review highlights current insights into mitochondrial metabolite transporters in CRC and their potential metabolic and epigenetic implications. Thus, elucidating the roles of these transporters may provide novel therapeutic strategies for CRC management.

Keywords:  Colorectal cancer; Metabolic reprogramming; Warburg effect; epigenetic; glutamine reliance; mitochondrial carriers

DOI:  https://doi.org/10.1007/s11033-026-12769-9
Sci Adv. 2026 Sep 18. 12(38): eaeh0227

Ubiquitin receptor-mediated, ubiquitin-independent targeted protein degradation via 26S proteasomes.

Seh Hoon Park, Yejin Jang, Soo-Yeon Lee, Eunseo Kim, Dawon Jeong, Insuk Byun, Jiseong Kim, Jisoo Yang, Chang-Han Lee, Dohyun Han, Jae-Hwan Nam, Min Jae Lee.

The 26S proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26S proteasomes without altering their structural or functional integrity. Protea-Tac with cognate antibodies degraded various target proteins, including c-Fos, BRD4, FlagTDP43, HAtau, and GFPODC. We mechanistically demonstrated that this platform is (i) modular, allowing facile target switching, (ii) Ub independent, and (iii) highly target specific. Furthermore, Protea-Tac exhibited potent in vivo antitumor efficacy, posttranslationally inducing c-Fos degradation and substantially delaying tumor progression through both viral and nonviral delivery systems. These findings identify Protea-Tac as a distinct TPD platform capable of directly degrading intracellular proteins via engineered 26S proteasomes.

DOI: https://doi.org/10.1126/sciadv.aeh0227
Front Immunol. 2026 ;17 1918556

Glycolysis and T cell-associated gene signature predicts prognosis and therapeutic responses in pancreatic cancer.

Wancheng Li, Dongao Fan, Yan Du, Lin Li, Wenjia Li, Wence Zhou.

   Background: Pancreatic cancer (PC) is a fatal malignancy, with glycolysis and T cells playing crucial roles in its pathogenesis. This study explored prognosis-related genes in glycolysis and T cells in PC using bioinformatics methods.
Methods: We first quantified distinct T-cell subsets via immune infiltration analysis of the TCGA-PAAD cohort and extracted T cell-related genes (T-RGs). Differentially expressed genes (DEGs) were obtained from GSE28735 and TCGA-PAAD. Intersecting these DEGs with T-RGs and glycolysis-related genes (G-RGs) yielded candidate genes. We screened prognostic genes using univariate Cox and LASSO regression, built a prognostic model in TCGA-PAAD and validated it in GSE57495. A nomogram was constructed for survival prediction, its reliability verified by calibration and ROC curves. We compared immune microenvironment, pathway enrichment, mutation landscape and drug sensitivity between high- and low-risk subgroups, and built lncRNA-miRNA-mRNA regulatory networks. In vitro and in vivo mouse tumorigenesis assays explored GPR87's potential involvement in glycolytic activity and CD8+ T cell infiltration. Seahorse analysis, glucose uptake detection and immunohistochemistry further explored roles in glucose metabolism and anti-tumor immunity.
Results: MET, KDELR3, AK4, and GPR87 were determined as prognostic genes. In the training set, this exploratory prognostic model showed moderate predictive performance, with area under the curve values of 0.72, 0.71, and 0.71 at 1, 2, and 3 years, respectively. The risk score and N-stage were identified as independent prognosis predictors, and the developed nomogram demonstrated moderate predictive performance. Functional pathways revealed enrichment in 44 pathways. There were 17 differential immune cells. In addition, risk scores were correlated with 28 immune checkpoints. The regulatory network comprised 26 miRNAs and 50 lncRNAs. Furthermore, computationally predicted correlations between prognostic genes and 60 drugs were identified in different risk groups. In vitro and in vivo experiments demonstrated that GPR87 knockdown inhibits the proliferation, migration, and clonogenic ability of PC cells while promoting their apoptosis. Furthermore, GPR87 expression was negatively correlated with CD8+ T cell, and GPR87 knockdown inhibited glycolysis in pancreatic cancer cells.
Conclusion: MET, KDELR3, AK4, and GPR87 were identified as candidate prognostic genes in PC, providing preliminary hypothesis-generating insights that require validation in independent institutional or prospective clinical cohorts before any clinical application.

Keywords:  GPR87; T cell; drug sensitivity; glycolysis; pancreatic cancer; prognosis

DOI:  https://doi.org/10.3389/fimmu.2026.1918556
Am J Physiol Cell Physiol. 2026 Sep 16.

Role of cardiac ion pumps, channels, and exchangers on regulation of mitochondrial bioenergetics.

David F Stowe, Amadou K S Camara.

  Membrane ion pumps and channels are essential key players in intracellular function and communication with other cells, e.g., nutrient uptake and bioelectrical communication. The cation exchangers Na+, H+, Ca2+ and K+ do more than simply rebalance ions and maintain ion homeostasis; they play crucial roles in modulating overall cellular bioenergetics. This review aims to describe how these cation gradients are formed and maintained by examining the ion flux mediated by each pump, channel, and exchanger and by integrating their functions across the cell and mitochondrial membranes. Most of this information is derived from the large amount of work in cardiac muscle cells where fluctuations in ion fluxes occur second by second. First is presented a review of the sarcolemmal and sarco(endo)plasmic reticular ion pumps, channels, and exchangers because mitochondrial ion fluxes are affected by the cytosolic ion concentrations. Then mitochondrial ion fluxes regulated by the mitochondrial ion pumps, channels, and exchangers are discussed. There are prior excellent reviews on mitochondrial cation fluxes, so the goal is to update the narrative with more recent publications that expand our understanding, with some controversies, of cell and mitochondrial cation fluxes on regulating a multitude of cell and organelle functions. Updates are furnished on the putative identity and function of the four major mitochondrial cation exchangers. Also, an emphasis is placed on updating the role of transmembrane ion fluxes on impacting mitochondrial bioenergetics by altering the proton motive force and oxidative phosphorylation. A few important historical reports are included with the recent studies.

Keywords:  Cardiac mitochondria; cardiac cell ion regulation; channels; exchangers; mitochondrial bioenergetics; mitochondrial ion pumps; sarcolemmal

DOI:  https://doi.org/10.1152/ajpcell.00305.2026
Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-76619-9
Nat Commun. 2026 08 06. pii: 9897. [Epub ahead of print]17(1):

A chromatin-informed transcriptional regulatory framework to stratify patients and guide therapy selection in triple-negative breast cancer.

Shalini Bahl, Nergiz Dogan-Artun, Julia Nguyen, Hassan Mahmoud, Wail Ba-Alawi, Seyed Ali Madani Tonekaboni, Komaldeep Kaur Kang, Meghan McGuire, Chantal Tobin, Jennifer Silvester, Paul Savage, Lucie Cressot, Ankita Nand, Guanqiao Feng, Paul Guilhamon, Arvind Singh Mer, Christopher Arlidge, Mitchell J Elliott, Morag Park, David W Cescon, Benjamin Haibe-Kains, Mathieu Lupien.

Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype with few effective targeted therapies and frequent resistance to chemotherapy. Here, we integrate transcriptional regulatory network inference with chromatin accessibility across a large-scale multi-system collection of primary tumors, patient-derived xenografts and model cell lines to quantify transcription factor activity and identify regulators that underpin triple-negative breast cancer identity. This approach prioritizes 94 high-confidence triple-negative breast cancer transcription factors whose activity capture inter-tumor heterogeneity and independently stratify patient outcome across clinical endpoints. Linking transcription factor activity to pharmacogenomic drug sensitivity profiles identifies reproducible drug-transcription factor associations across independent datasets, including NFE2L3 and CBFB activity as predictors of sensitivity to mTOR inhibition, which we validate in everolimus-treated triple-negative breast cancer patient-derived xenograft models. Collectively, we provide a transcriptional and chromatin-informed framework to capture triple-negative breast cancer regulatory state and expand transcription factor guided precision medicine to this breast cancer subtype.

DOI: https://doi.org/10.1038/s41467-026-76385-8
Nat Metab. 2026 Sep 15.

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

DOI: https://doi.org/10.1038/s42255-026-01616-7
Nat Commun. 2026 Aug 14. pii: 9761. [Epub ahead of print]17(1):

A permeable protein nanocage enables facile cargo loading and cytosolic protein delivery.

Seokmu Kwon, Michael P Andreas, Jesse A Jones, Tobias W Giessen.

The cytosolic delivery of therapeutic proteins remains one of the most persistent challenges in modern drug delivery. Here, we report the discovery and characterization of an encapsulin-based protein nanocage, QtEnc, with unexpected permeability properties and the ability to internalize cargo proteins in vitro, fundamentally departing from existing protein nanocage cargo loading paradigms. This permeability enables simple, rapid, and single-step post-assembly cargo loading, accommodating cargos as large as 482 kDa, and allowing multiplexed cargo co-encapsulation with tunable ratios. Leveraging this property, we develop a modular QtEnc-based NanoCarrier (QtEncNC) with a pH-responsive cargo detachment module and an endosomal escape module, enabling low pH-triggered cargo release from assembled shells and subsequent endosomal escape for cytosolic delivery. Using a cytotoxic protein, BLF1, as a proof-of-concept QtEncNC payload, we demonstrate efficient cytosolic protein delivery in HeLa cells. These findings establish QtEncNC as a versatile and modular platform for cytosolic protein delivery with broad biomedical potential.

DOI: https://doi.org/10.1038/s41467-026-76849-x