bims-miptne 2026-10-04 papers

Blood. 2026 Oct 01. pii: blood.2025032930. [Epub ahead of print]

Inhibition of mitochondrial permeability transition selectively suppresses thrombogenic platelet procoagulant activity.

Platelets support coagulation by externalizing phosphatidylserine (PS), creating a catalytic surface for thrombin generation and fibrin formation. Although platelet PS exposure is required for hemostasis, excessive procoagulant platelet activity drives thrombosis. Sustained calcium influx after strong agonist stimulation promotes mitochondrial permeability transition pore (mPTP) opening, mitochondrial depolarization and calcium amplification that commit platelets to PS-high procoagulant states. Existing approaches to suppress this pathway are limited by the hemostatic requirement for platelet PS exposure and pleiotropic effects of cyclophilin-targeting agents. Here, we use a series of newly developed cyclophilin D-independent small molecule mPTP inhibitors to define how mPTP opening regulates procoagulant platelet activity. Under GPVI/PAR-driven procoagulant conditions, MC63, TR001 and TR002 preserved mitochondrial membrane potential, prevented intracellular calcium overload and reduced PS/P-selectin-positive platelets, microparticle release and membrane blebbing, while preserving agonist-induced calcium mobilization, secretion, integrin activation, aggregation, F-actin assembly and clot retraction. Mechanistically, mPTP inhibition limited calcium-dependent phosphatase, protease and mitochondrial activities associated with procoagulant platelet conversion. MC63, TR001 and TR002 reduced platelet-dependent thrombin generation and fibrin formation without affecting platelet-independent thrombin activity. In whole blood perfused over collagen, mPTP inhibitors reduced PS-positive platelets within thrombi without impairing platelet accumulation. In vivo, mPTP inhibitors decreased platelet and fibrin accumulation after laser-induced arteriolar injury but did not prolong tail bleeding alone or in combination with acetylsalicylic acid. Together, these findings identify mPTP opening as a druggable checkpoint for platelet procoagulant commitment and support mPTP inhibition as an antithrombotic strategy that may preserve hemostasis.

DOI: https://doi.org/10.1182/blood.2025032930

Mitochondrion. 2026 Oct 01. pii: S1567-7249(26)00111-X. [Epub ahead of print] 102221

Mitochondria and associated complexes as therapeutic targets in aging: From biomacromolecular structure-function insights to clinical translation.

Xiaofang Zhang, Tao Tao, Wanyi Liu, Aitong Xie, Youcai Liang, Xiao Zhu.

Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into how structural and functional disruptions of these complexes drive cellular senescence and systemic decline. We outline the architecture of mitochondrial assemblies (e.g., oxidative phosphorylation (OXPHOS) complexes, mtDNA-protein interactions) essential for energy production and organelle stability. Age-related alterations in stoichiometry, conformational states (e.g., mPTP opening), and post-translational modifications (e.g., SIRT3-mediated acetylation) compromise mitochondrial integrity, fueling metabolic dysfunction and chronic inflammation ("inflammaging"). Therapeutic strategies include small-molecule stabilizers of ETC supercomplexes, peptide-based mPTP inhibitors, and CRISPR-mediated correction of mtDNA-protein mismatches. Tissue-specific models (e.g., Complex I in skin aging, Bcl-2 protein imbalance in ovarian aging) exemplify the clinical relevance. We also categorize nine age-associated diseases-neurodegenerative, cardiovascular, and cancer types-based on their dependence on distinct mitochondrial complexes, such as ATP synthase in cancer resistance and the TIM/TOM import machinery in Alzheimer's disease. By linking structural findings (e.g., cryo-EM studies) with therapeutic innovation, this review offers a framework for targeting mitochondrial complexes to mitigate aging and its related pathologies.

Keywords: Aging; Aging-related diseases; Mitochondria; Therapy; mtDNA

DOI: https://doi.org/10.1016/j.mito.2026.102221

Science. 2026 Oct;394(6819): eadz4797

Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.

Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.

Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.

DOI: https://doi.org/10.1126/science.adz4797

Cell. 2026 Oct 01. pii: S0092-8674(26)01068-8. [Epub ahead of print]189(20): 6307-6324.e7

Acanthamoeba ATP synthase structure reveals the TCA cycle is tethered to OXPHOS.

MitoCarta Tree of Life Consortium

Oxidative phosphorylation (OXPHOS) is a key metabolic process that couples redox energy to ATP production. While some core OXPHOS complex subunits are found across all domains of life, many have diverged or expanded across evolution-as seen in the protozoan pathogen Acanthamoeba castellanii. By integrating cryo-electron microscopy of unenriched mitochondrial lysate with mass spectrometry proteomics, we resolved the structures of endogenous mitochondrial ATP synthase (complex V), Hsp60, and respiratory complex III from Acanthamoeba. We capture Acanthamoeba ATP synthase in an IF1-inhibited state and reveal how Acanthamoeba-specific subunits and extensions stabilize the molecular machine, which includes a β subunit extension that interfaces with the peripheral stalk. Additionally, we characterize an active malate dehydrogenase (MDH) dimer structurally integrated within the ATP synthase peripheral stalk, thus revealing a direct protein tether between OXPHOS and the tricarboxylic acid cycle. Together, these findings provide structural insight into lineage-specific adaptations in Acanthamoeba that may tune protozoan metabolism.

Keywords: ATP synthase; Acanthamoeba; complex V; cryo-EM; crystallography; malate dehydrogenase; mitochondria; oxidative phosphorylation; respiratory complexes; tricarboxylic acid cycle

DOI: https://doi.org/10.1016/j.cell.2026.08.057

Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2627537123

Step-by-step maturation mechanism of the binary toxin pore revealed by cryo-EM analysis.

Tomohito Yamada, Ren Nakanishi, Yukihiko Sugita, Yuki Ninomiya, Toru Yoshida, Takeshi Noda, Hideaki Tsuge.

Membrane pore-forming proteins (PFPs) form ring-shaped membrane-translocating oligomers on membranes, contributing to infection, immunity, and cell death functions. Binary toxins produced by some bacteria consist of an enzymatic component that acts as a toxin and a membrane-binding component that forms a pore that delivers the enzymatic component into target cells. Cryoelectron microscopy (cryo-EM) has advanced our understanding of these translocation mechanisms by revealing several binary toxin complexes' structures. However, the mechanisms underlying the initial pore formation remain unclear. We determined the structures of several oligomeric forms of the membrane-binding component Ib of the iota toxin from Clostridium perfringens at various stages of pore formation. Structural comparisons revealed how the symmetrically arranged soluble oligomer (prepore) asymmetrically matures into a transmembrane oligomer (pore). These findings enhance our understanding of mechanisms of PFP and provide a structural basis for developing nanodevices using membrane pores.

Keywords: binary toxin; cryo-EM; pore; pore maturation

DOI: https://doi.org/10.1073/pnas.2627537123