bims-miptne 2026-08-02 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–08–02
seven papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mechanistic Modeling of MCUx Gatekeeping, Ca2+ Transport, and Coupled Cytosolic-Mitochondrial Ca2+ Dynamics.
Matrix polyamines regulate bidirectional calcium flux through MCU.
Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.
Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Igniting antitumour immunity with cancer cell pyroptosis.
Structures of the sodium-coupled phosphate importer SLC34A2 reveal a distinct architecture and gating mechanism.

Am J Physiol Cell Physiol. 2026 Jul 29.

Mechanistic Modeling of MCUx Gatekeeping, Ca2+ Transport, and Coupled Cytosolic-Mitochondrial Ca2+ Dynamics.

Yisak D Asefa, Devanshi D Dave, Said H Audi, Dexuan Xie, Xiaowen Bai, Allen W Cowley, Ranjan K Dash.

  Mitochondrial Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUx), in which MICU1/2 serve as cytosolic Ca2+-sensing gatekeepers that set a Ca2+-dependent activation threshold. Coordinated control of MCUx activity is critical because mitochondrial Ca2+ uptake couples cytosolic Ca2+ signals to metabolic activation and must be regulated to prevent mitochondrial Ca2+ overload and bioenergetic dysfunction. We developed a mechanistic model that incorporates explicit MICU1/2-dependent MCUx gatekeeping and a thermodynamically constrained Ca2+ transport formulation that accounts for Mg2+ inhibition and membrane potential dependence. Cytosolic and mitochondrial Ca2+ dynamics were simulated by integrating the MCUx model into a mitochondrial cation-handling model under multiple Ca2+ stimulation protocols. Because matrix-side Ca2+ regulation of MCUx remains controversial, we also evaluated a putative matrix-side regulatory mechanism by comparing simulations with and without an added matrix-side regulatory module, rather than assuming such regulation as a required feature of the MCUx model. The model reproduces key experimental behaviors across genotypes. In wild-type mitochondria, MCUx-mediated Ca²⁺ uptake is negligible below a cytosolic Ca2+ threshold (~0.2 µM), whereas MICU1-knockout mitochondria show constitutive uptake and MICU2-knockout mitochondria exhibit an intermediate, lowered threshold. Inclusion of matrix-side MCUx regulation transiently attenuated MCUx-mediated Ca²⁺ uptake over an intermediate mitochondrial Ca2+ range, producing higher transient cytosolic Ca2+ and lower transient mitochondrial Ca2+, while both cases approached similar steady states. In addition, cytosolic Mg2+ acts as a graded inhibitor of MCUx-mediated Ca2+ uptake, limiting mitochondrial Ca2+ loading. These results provide a quantitative framework for coupled cytosolic-mitochondrial Ca²⁺ dynamics across diverse conditions.

Keywords:  Cytosolic-mitochondrial Ca2+ dynamics; MCUx gating; MICU1/2 regulation; Mitochondrial Ca2+ uptake; Mitochondrial calcium uniporter complex (MCUx)

DOI:  https://doi.org/10.1152/ajpcell.00204.2026
Structure. 2026 Jul 27. pii: S0969-2126(26)00212-1. [Epub ahead of print]

Matrix polyamines regulate bidirectional calcium flux through MCU.

Qinzhe Wang, Enrique Balderas, Alejandro Jara Ramos, Ashley Nwafor, Jack S McManus, Neeraj K Rai, Yasmin B Masini, David R Eberhardt, Emma C Rekate, Anthony M Balynas, Xue Yin, Tracy Murray Stewart, Erhu Cao, Anna Stary-Weinzinger, Dipayan Chaudhuri.

  Polyamines, well-known regulators of the mitochondrial calcium (Ca2+) uniporter channel, show unexpected effects when binding the channel from within the matrix. Using cryo-EM, molecular dynamics simulations, and mutagenesis experiments, we determine that polyamines achieve such regulation by binding within the pore to a ring of negative residues forming a matrix gate, inhibiting Ca2+ conduction. In whole-mitoplast electrophysiology assays, matrix polyamines cause a gradual increase in Ca2+ currents during prolonged conduction, due to relief of this inhibition. Notably, this electrostatic binding increases 3-fold as the inner membrane depolarizes, preventing Ca2+ efflux. Additionally, we also identify that phospholipids form part of the Ca2+ conduction pathway through MCU. Because we find significant variability in matrix polyamine content across mouse organs, this unexpected mechanism for sculpting the mitochondrial Ca2+ waveform suggests a tissue-specific regulation of metabolism.

Keywords:  MCU; calcium channels; disinhibition; inward rectification; mitochondrial calcium uptake; polyamine; putrescine; spermidine; spermine

DOI:  https://doi.org/10.1016/j.str.2026.07.002
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2608102123

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals.

Jingwen Chen, Lili Su, Bangze Pan, Junhao Sang, Linlin Li, Junsong Huang, Zhao-Lan Hu, Lixin Wang, Xiaojie Zhang, Jun Jin.

  Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8+ T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

Keywords:  T cell aging; cryo-electron tomography; mitoribosome

DOI:  https://doi.org/10.1073/pnas.2608102123
iScience. 2026 Aug 21. 29(8): 116788

Oxygen-stable streptolysin O variant enables mitochondrial ATP synthesis analysis in minimal cells blood and tissues.

Makoto Fujikawa, Natsuhiko Yamada, Shuhei Yasuda, Tsutomu Tanabe, Kenta Maruyama.

  Quantifying mitochondrial ATP synthesis remains inaccessible in rare cells, blood, and microdissected tissues because of the biochemical instability of streptolysin O (SLO)-based permeabilization. Here, we introduce an oxygen-stable SLO variant, streptolysin O tolerant (SLOT), and an improved mitochondrial ATP synthesis capacity (iMASC) assay to enable sensitive analysis across diverse samples. SLOT combines non-essential N-terminal deletion (Δ1-77) with a C530A substitution, conferring reductant-independent activity and long-term stability. Temperature-controlled activation restricts permeabilization to the plasma membrane, preserving mitochondrial function. iMASC assay supports continuous measurement for more than 1 h from 10 to 20 cells and applies to adherent and suspension cells, whole blood, and microdissected tissues. Using this platform, we identify platelets as dominant contributors to glycerol-3-phosphate-driven ATP synthesis in murine blood and enable sequential dissection of respiratory chain and ATP synthase activities within single tissues. This framework establishes a broadly applicable approach for mitochondrial metabolism analysis.

Keywords:  SLOT; iMASC assay; improved mitochondrial ATP synthesis capacity assay; mitochondrial ATP synthesis; mitochondrial metabolism; rare and complex biological samples; respiratory chain complexes; streptolysin O tolerant; temperature-controlled permeabilization; whole blood

DOI:  https://doi.org/10.1016/j.isci.2026.116788
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
Nat Rev Cancer. 2026 Jul 27.

Igniting antitumour immunity with cancer cell pyroptosis.

Xin Liu, Elena Goldberg, Jonathan C Kagan, Hao Wu.

Gasdermins (GSDMs) are a family of pore-forming proteins that execute pyroptosis, a lytic form of programmed cell death associated with membrane rupture. This function of GSDMs was initially identified from studies of gasdermin D (GSDMD), which is cleaved and activated by inflammatory caspases in the inflammasome pathway. It is now established that other eukaryotic or pathogen-encoded proteases, as well as post-translational modifications, can also activate GSDM family members independent of inflammasomes and in multiple cell types including cancer cells. T cell granzyme-mediated GSDM activation, exogenous delivery of active GSDMs, and small molecule-induced activation of GSDMs in cancer cells have been shown to promote antitumour immunity through pyroptosis. Notably, only a fraction of cancer cells needs to undergo pyroptosis to induce immune cell infiltration and antitumour immunity with tolerable toxicity. Here, we summarize current knowledge on the role of pyroptosis in antitumour immunity, discuss pyroptosis in the context of other lytic forms of cell death, and provide an outlook on how cancer cell pyroptosis may synergize with existing immunotherapies.

DOI: https://doi.org/10.1038/s41568-026-00959-3
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602077123

Structures of the sodium-coupled phosphate importer SLC34A2 reveal a distinct architecture and gating mechanism.

Qinyu Zhu, Omar Almakki, Melinda M Diver.

  Dysregulation of inorganic phosphate (Pi) homeostasis contributes to metabolic disease, cancer, pathological calcification, and kidney disease. Systemic phosphate balance is regulated by SLC34 transporters that mediate renal Pi retention (SLC34A1/A3) and intestinal dietary Pi absorption (SLC34A2). SLC34s couple Pi uptake to the symport of sodium (Na+) down its electrochemical gradient. Mutations or altered expression of SLC34 proteins are linked to disorders such as chronic kidney disease, where hyperphosphatemia is a major complication, and the lung disease pulmonary alveolar microlithiasis, caused by inactivating SLC34A2 mutations. SLC34A2 is also overexpressed in most ovarian and uterine tumors, making it an attractive target for antibody-drug conjugates. We present cryoelectron microscopy structures of SLC34A2 when the transporter is empty, bound to Na+ ions only, fully loaded with Na+ ions and Pi, and bound to an inhibitor phosphonoformic acid, revealing its distinct architecture, substrate and ion binding sites, the role of Na+, and multiple transporter states. Pi binds at a highly symmetric, membrane-embedded pocket positioned approximately mid-membrane and is coordinated by its signature four residue QSSS repeat motifs. Na+ shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state. Integrated with functional analyses, these structures reveal that SLC34 transporters operate through an atypical alternating access cycle defined by coordinated elevator movements of an auxiliary gate domain. This work lays a foundational framework for understanding Pi regulation and opens avenues for therapeutic strategies targeting disorders linked to phosphate imbalance.

Keywords:  SLC34 Na+-driven phosphate importer family; chronic kidney disease (CKD); pulmonary alveolar microlithiasis (PAM); systemic phosphate homeostasis; transporter mechanisms

DOI:  https://doi.org/10.1073/pnas.2602077123