bims-miptne 2026-09-13 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–09–13
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Vitamin C is a physiological modulator for mitochondrial calcium uptake.
InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity.
Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.
An operational perturbation proteomics-based virtual cell model.
Mechanism of membrane perforation in rotavirus cell entry.
Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.
Nucleoporins in Cancer: Functional Roles and Therapeutic Opportunities.

Biochem Biophys Res Commun. 2026 Sep 02. pii: S0006-291X(26)01300-8. [Epub ahead of print]835 154536

Vitamin C is a physiological modulator for mitochondrial calcium uptake.

Jialong Li, Kozo Hamada.

  Mitochondrial calcium homeostasis is critical for bioenergetics, cell signaling, and cell survival and death, but its regulatory mechanism remains largely unknown. Here, a mitochondria-targeted genetically encoded calcium indicator has revealed that physiological concentrations of ascorbic acid (vitamin C) suppress mitochondrial calcium uptake in both intact living cells and permeabilized cells and enhance intracellular calcium signaling compared with ascorbate-deprived conditions. Mechanistic analyses indicate that this effect is mediated by a reduction in mitochondrial membrane potential, the primary driving force for mitochondrial calcium uptake. These findings uncover an unrecognized role of ascorbic acid in mitochondrial calcium homeostasis. Given the roles of mitochondrial calcium in neurodegeneration and cancer cell bioenergetics, our findings provide new insights into disease pathophysiology and potential therapeutic strategies.

Keywords:  Ca(2+) signaling; Genetically encoded Ca(2+) indicator; Mitochondria-associated ER membranes; Mitochondrial Ca(2+) homeostasis; Mitochondrial Ca(2+) uniporter; Mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.bbrc.2026.154536
Nat Commun. 2026 Aug 13. pii: 9729. [Epub ahead of print]17(1):

InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity.

Gaomin Feng, Elizabeth M Ruark, Alexandra G Mulligan, Eric K F Donahue, Anthony L Hoang, Brianne Jacquet-Cribe, Li Peng, Kristopher Burkewitz.

Certain forms of mitochondrial impairment confer longevity, while disease-associated mitochondrial dysfunction triggers pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. To explain this connection, we test multiple candidate links between Ca2+ and mitochondrial homeostasis previously established in vitro, including mitochondrial calcium uniporter (MCU)-dependent stimulation of respiration and cytosolic pathways regulating mitochondrial dynamics. We find that MCU is dispensable for both respiration and longevity in Complex I mutants. Conversely, transcriptomic profiling and imaging reveal InsP3R impairment results in maladaptive expansion of compromised mitochondrial networks. We provide evidence that this aberrant mitochondrial expansion results from disruption of a conserved, InsP3R-dependent actin remodeling network centered on Arp2/3. Disruption of actin remodeling or autophagy mimics the mitochondrial expansion and longevity suppression of InsP3R mutants. Conversely, driving mitochondrial fragmentation ameliorates mitochondrial expansion and rescues longevity in InsP3R mutants, supporting a model in which InsP3R-dependent actin remodeling is required for segregation and clearance of mitochondria. These findings identify an inter-organelle signaling axis linking ER calcium release and cytoskeletal remodeling to adaptive mitochondrial responses associated with longevity.

DOI: https://doi.org/10.1038/s41467-026-76514-3
Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]

Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.

Charles Ng, Tak Shun Fung, Dayi Li, Korbinian N Kropp, Luis F Somarribas Patterson, Alexandria Markovitz, Daniel N Weinberg, Olivia Jones, Ji-Young Kim, Guoan Zhang, Richard Koche, Mara Monetti, Huayuan Tang, Yun He, Zhengshuang Xu, Xin Cai, Ziqi Yu, Geetha Bhagavatula, Sean P Colgan, Ya-Hui Lin, Zhuoning Li, Elizabeth M Steinert, Christopher A Klebanoff, Santosha A Vardhana, Navdeep S Chandel, Lin Wu, Craig B Thompson.

  Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

Keywords:  BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology

DOI:  https://doi.org/10.1016/j.cell.2026.08.023
Nature. 2026 Sep 09.

An operational perturbation proteomics-based virtual cell model.

Rui Sun, Liujia Qian, Yongge Li, Tong Liu, Honghan Cheng, Xuedong Zhang, Xueya Zhou, Yuecheng Zhan, Guangmei Zhang, Zhengchao Luo, Kunpeng Ma, Chunlong Wu, Dongchen Ji, Zhangzhi Xue, Hongxue Meng, Yuhang Xiang, Dingwei Lei, Qianhe Zhou, Wenbin Hu, Yuhan Deng, Lingling Tan, Qi Xiao, Zhiwei Liu, Lei Zeng, Liqin Qian, Xuan Zheng, Qiong Hu, Nianzi Luo, Weinan E, Peijie Zhou, Han Wen, Yi Zhu, Tiannan Guo.

Artificial intelligence-empowered virtual cell models represent an emerging approach for in silico drug discovery1-3, yet most existing approaches lack large-scale, time-resolved perturbation proteomics data and interpretable frameworks for predicting therapeutic responses. Here we generated more than 38 million temporal protein-abundance measurements from systematically perturbed breast cancer cell lines, and developed ProteinTalks, a virtual cell model. Central to ProteinTalks is the synergy of this large-scale dynamic proteomic resource and the model architecture, enabling a new pretraining framework that learns transferable dynamical latent representations from temporal proteome trajectories. By modelling how proteins respond conditionally to different perturbations, this approach enables the model to function as an operational tool for diverse drug discovery tasks: predicting drug efficacy and synergy, discovering new drug combinations, probing proteins associated with drug resistance, stratifying patient responses and prioritizing drug candidates for patient organoids. It also shows robust transferability, extending beyond cell lines to patient-derived organoids and clinical biopsies, generally achieving higher performance than the selected benchmark implementations under the evaluated protocols. Together, ProteinTalks shows how scalable pretraining of transferable dynamic representations enables operational, dynamics-aware, proteomics-based virtual cell models to advance in silico drug discovery.

DOI: https://doi.org/10.1038/s41586-026-11001-9
Science. 2026 Sep 10. 393(6816): 1128-1133

Mechanism of membrane perforation in rotavirus cell entry.

Marilina de Sautu, Conny Leistner, Tomas Kirchhausen, Simon Jenni, Stephen C Harrison.

Cell entry of nonenveloped animal viruses requires translocation of a macromolecular assembly across a cellular membrane. Double-stranded RNA viruses introduce into the target cell an inner capsid particle that does not uncoat further. Instead, it extrudes capped viral mRNA by virtue of polymerase and capping activities within it. As described here, we used cryogenic electron tomography to visualize the full course of rhesus rotavirus entry, from cell attachment and virion uptake to release of the subviral particle. The cryo-tomograms and subtomogram averaging of classified subparticles link high-resolution structures of the virion and its components with time series from live-cell fluorescence microscopy. We outline the mechanism of each step in the entry process, including the membrane perforation step that transfers a subviral particle into the cytosol.

DOI: https://doi.org/10.1126/science.aeg4851
Oncogene. 2026 Sep 11.

Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.

Weidong Yu, Bo Wang, Fanhao Meng, Xiaojun Ren, Danyi Zhou, Huanxin Wei, Zhengquan Yang, Hongwei Sun, Minghua Jiang, Tao Xia, Wei Cui, Hezhi Fang.

Pancreatic ductal adenocarcinoma (PDAC) cells rely on fatty acid oxidation (FAO) for proliferation; however, the regulatory mechanisms governing this dependency and their clinical implications remain unclear. Here, we report that PDAC patients exhibit decreased plasma levels of propionyl-CoA intermediates, alongside accelerated propionyl-CoA catabolic activity within both human PDAC tumors and Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) mouse tumors. Specifically, PDAC cells upregulate propionyl-CoA carboxylase (PCC) to accelerate propionyl-CoA catabolism, thereby establishing a metabolic signature distinct from that of healthy tissues. Mechanistically, PCC is essential for PDAC growth, not by fueling the TCA cycle, but by preventing toxic propionyl-CoA accumulation. We further demonstrate that elevated propionyl-CoA leads to the propionylation-induced inactivation of the mitochondrial fatty acid oxidation (FAO) enzyme ACAA2 at Lysine 137, thereby blocking the FAO flux required for tumor proliferation. Moreover, high PCCA expression in patient PDAC tumors is significantly associated with decreased lipid accumulation, and PDAC cells with high PCC levels are more sensitive to etomoxir-induced cell proliferation arrest. These findings establish the PCC-ACAA2 axis as a critical metabolic vulnerability and a promising target for diagnostic and therapeutic interventions in PDAC.

DOI: https://doi.org/10.1038/s41388-026-03979-3
Cancer Discov. 2026 Sep 09. OF1-OF12

Nucleoporins in Cancer: Functional Roles and Therapeutic Opportunities.

Perumalraja Kirthika, Vijayakumar Jawalagatti, Marc Carceles-Cordon, Josep Domingo-Domenech, Veronica Rodriguez-Bravo.

The nuclear pore complex (NPC) and its building-block proteins, nucleoporins (NUP), play fundamental roles in maintaining cellular fitness by regulating nucleocytoplasmic transport, chromatin and transcriptional activity, and genome stability. These core biological processes are critical for cancer cells, and thus, tumor-driven co-option of NUP-regulated functions has emerged as an important mechanism contributing to the pathogenesis of multiple malignancies. This review discusses how NUP dysregulation mechanistically contributes to tumor initiation and progression and how these insights open opportunities for innovative anticancer therapies, including using clinical-grade molecular glues that induce selective NUP degradation and pharmacologically inhibiting NPC-regulated epigenomic/transcriptomic signaling and nucleocytoplasmic transport.
SIGNIFICANCE: Recent studies demonstrate that NUPs play fundamental roles in cancer pathogenesis by dysregulating key NPC functions and driving tumorigenesis and disease progression. NUPs and NPC-regulated mechanisms can be pharmacologically targeted, providing a strong rationale for developing much-needed innovative therapeutic strategies to combat cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0347