bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2025–01–26
three papers selected by
Gavin McStay, Liverpool John Moores University
  1. Insight into copper coordination in O2 reduction by water-soluble cytochrome c oxidase models.
  2. Mitochondrial protein import stress.
  3. Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis.
  1. Dalton Trans. 2025 Jan 21.
    Insight into copper coordination in O2 reduction by water-soluble cytochrome c oxidase models.
    Mathilde Berthe, Corinne Boudon, Nolwenn Le Breton, Hiroaki Kitagishi, Koji Oohora, Takashi Hayashi, Jennifer A Wytko, Jean Weiss.
      Iron-copper complexes have been extensively studied in the search for efficient cytochrome c oxidase models. Whereas most dinuclear materials usually focus on fine-tuning the coordination of heme-Fe, this work shows that the coordination of copper in cytochrome c oxidase models should be carefully taken into consideration. A β-cyclodextrin dimer was built around a bipyridine linker and combined with Fe-tetraphenylsulfonatoporphyrinate (FeTPPS) to generate a self-assembled hydrosoluble cytochrome c oxidase model. Cyclic voltammetry and rotating ring disk electrode experiments showed that this model with a tetrahedral coordination of copper(I) is efficient for the reduction of molecular oxygen with an average of 3.6 electrons indicating a preference and efficiency for the four-electron reduction to water.
    DOI:  https://doi.org/10.1039/d4dt03188a
  2. Nat Cell Biol. 2025 Jan 22.
    Mitochondrial protein import stress.
    Nikolaus Pfanner, Fabian den Brave, Thomas Becker.
      Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.
    DOI:  https://doi.org/10.1038/s41556-024-01590-w
  3. Pharmacol Res. 2025 Jan 21. pii: S1043-6618(25)00045-3. [Epub ahead of print] 107620
    Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis.
    Jiaqi Yao, Yuhong Jiang, Pengcheng Zhang, Yifan Miao, Xiajia Wu, Hang Lei, Zhijun Xie, Yong Tian, Xianlin Zhao, Juan Li, Lv Zhu, Meihua Wan, Wenfu Tang.
      The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis. Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.
    Keywords:  Caerulein (PubChem CID: 16129675); Emodin; Emodin (PubChem CID: 3220); FCCP (PubChem CID: 3330); Histidine triad nucleotide-binding protein 2; Mitochondrial oxidative phosphorylation; Taurocholic acid sodium salt hydrate (PubChem CID: 23687511), Taurocholic acid 3-sulfate (PubChem CID: 92043494); acute pancreatitis; pancreatic acinar necrosis
    DOI:  https://doi.org/10.1016/j.phrs.2025.107620
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