{
  "abstract": "Growing evidence indicates that cancer cell mitochondria remain functional and represent attractive therapeutic targets. Mitochondria-targeted drug delivery commonly uses triphenylphosphonium (TPP + )-conjugated compounds, which preferentially accumulate in cancer cell mitochondria because of their highly negative membrane potential. Many TPP + -conjugated agents inhibit mitochondrial electron transport chain complexes I and II, suppressing mitochondrial respiration and cancer cell proliferation. Recent studies suggest that electronwithdrawing substituents, such as trifluoromethyl groups, on the TPP + phenyl rings alter electron density around the phosphorus center, enhancing mitochondrial uncoupling activity and antiproliferative effects. To determine how TPP + electronic substituents influence redox properties, mitochondrial complex III interactions, and biological activity, we used mitochondria-targeted atovaquone (Mito-ATO) as a model system.\n\nAtovaquone (ATO), a hydroxy-1,4-naphthoquinone and the only FDA-approved mitochondrial complex III inhibitor, is currently undergoing clinical evaluation for cancer therapy. We synthesized a series of mitochondriatargeted ATO derivatives (MitoR-ATOs) containing electron-donating or electron-withdrawing substituents on the TPP + moiety. Their effects on enzymatic superoxide generation were assessed by EPR spin trapping, mitochondrial oxygen consumption by Seahorse XF96 analysis, complex III Qi-site binding by computational modeling, and cancer cell proliferation using IncuCyte live-cell imaging. Unexpectedly, several MitoR-ATO derivatives emerged as potent complex III inhibitors through enhanced binding at the Qi site.\n\nStructure-activity relationship analysis revealed that the intrinsic redox properties of TPP + -conjugated MitoR-ATO analogs alone do not predict biological activity. Instead, accurate prediction of the therapeutic efficacy of mitochondria-targeted complex III inhibitors requires integrating redox properties with computational analyses of ligand-protein interactions at the mitochondrial complex III Qi site.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Bruna Rafaela Pereira Resende"
    },
    {
      "name": "Gang Cheng"
    },
    {
      "name": "Gabriel Canard"
    },
    {
      "name": "Didier Siri"
    },
    {
      "name": "Vanessa Leone"
    },
    {
      "name": "Micael Hardy"
    },
    {
      "name": "Balaraman Kalyanaraman"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6yvznxzcsdyj6.bib",
  "cited_by": 1,
  "doi": "10.1016/j.redox.2026.104370",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S2213231726003691",
  "id": "6yvznxzcsdyj6",
  "issns": [
    "2213-2317"
  ],
  "landing_url": "https://hal.science/hal-05769164v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.chim"
    ],
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "R5-920"
    ],
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7196964989",
  "pdf_url": "https://hal.science/hal-05769164/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/6yvznxzcsdyj6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "hal-05769164",
      "source": "hal",
      "url": "https://hal.science/hal-05769164v1"
    },
    {
      "first_seen": "2026-10-30T13:43:15Z",
      "native_id": "9bb08a57f3e54b3c99f13eb1402dd35c",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.redox.2026.104370"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Redox and structural determinants of mitochondrial complex III inhibition by triphenylphosphonium-conjugated atovaquone analogs",
  "title_text": "Redox and structural determinants of mitochondrial complex III inhibition by triphenylphosphonium-conjugated atovaquone analogs",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:15Z",
  "url": "https://research.draconitic.com/paper/6yvznxzcsdyj6",
  "venue": "Redox Biology",
  "versions": []
}