{
  "abstract": "Mitochondrial NADH-ubiquinone (UQ) oxidoreductase (respiratory complex I) reduces UQ within its long tunnel-like cavity, which is coupled to triggering proton translocation at the membrane domain. Although mammalian complex I adopts distinct \"open\" and \"closed\" conformations, the architecture of the UQ-accessing tunnel in the open conformation remains poorly defined owing to partial disorder of the UQ catalytic region near Fe-S cluster N2 in the tunnel. Here, we applied cryo-electron microscopy (EM) single particle analysis to determine the structures of complex I in bovine heart submitochondrial particles in the presence or absence of a mycothiazole-type inhibitor. Preceding photoaffinity labeling experiments using a synthetic photoreactive derivative ([125I]pMT) revealed that mycothiazole specifically labels the 49-kDa and ND1 subunits, both of which form a part of the UQ-accessing tunnel. Cryo-EM analysis demonstrated that bound mycothiazole reorganizes and stabilizes the UQ catalytic region in both open and closed conformations, enabling the first complete structural modeling of the entire UQ-accessing tunnel in the open conformation. Unexpectedly, in the presence of bound mycothiazole, loops of the PSST subunit forming the catalytic region in the tunnel adopted closed conformation-like features, whereas open conformation-like features were determined for the transmembrane helices of ND1 and ND6 subunits. The present study revealed that bound mycothiazole can reorganize the UQ catalytic region in the UQ-accessing tunnel and lead to a hybrid conformational state beyond the canonical open-versus-closed conformational model.",
  "abstract_shown": true,
  "affiliations": [
    "Kyoto University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "S. Akisada"
    },
    {
      "name": "R. Otani"
    },
    {
      "name": "T. Masuya"
    },
    {
      "name": "S. Miyako"
    },
    {
      "name": "H. Saito"
    },
    {
      "name": "K. Mitsuoka"
    },
    {
      "name": "H. Miyoshi"
    },
    {
      "name": "K. Yokoyama"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Murai"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cn7g1erfg1882.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.01.756109",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756109v1.full",
  "id": "cn7g1erfg1882",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756109v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ],
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7220461843",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756109v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cn7g1erfg1882.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:02Z",
      "native_id": "10.64898/2026.10.01.756109",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.01.756109v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Mycothiazole enables structural characterization of entire ubiquinone-accessing tunnel in mitochondrial respiratory complex I",
  "title_text": "Mycothiazole enables structural characterization of entire ubiquinone-accessing tunnel in mitochondrial respiratory complex I",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:02Z",
  "url": "https://research.draconitic.com/paper/cn7g1erfg1882",
  "venue": "bioRxiv",
  "versions": []
}