{
  "abstract": "Maintenance of fissed mitochondria is viewed as a defining feature of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers. However, regulation of this process by accompanying comutations or environmental factors is not clearly defined. Here, by analyzing a subset of pancreatic cancer lesions driven by concurrent Kras G12D and GNAS complex locus gene (GNAS R201C/H ) mutations, we found that despite the presence of mutant Kras, hyperactive Gnas R201C maintains mitochondria predominantly in a fused state, which is necessary for tumor growth. Multiplex proteomics, super-resolution microscopy, loss- and gain-of-function studies, coupled with metabolite rescue experiments, revealed that Gnas R201C -regulated branched-chain amino acid (BCAA) pathway is a previously unidentified regulator of mitochondrial morphology. Mechanistically, the BCAA pathway, the associated tricarboxylic acid cycle, and aspartate metabolism converge on nicotinamide adenine dinucleotide (NADH-NAD + ) metabolites to promote mitochondrial elongation. NAD + availability is crucial for mitochondrial fusion, as facilitating NAD + generation through alternative means promotes fusion. Collectively, we unraveled a new mechanism that drives mitochondrial fusion and showed that the combination of oncogenic signaling and metabolism can maintain distinct mitochondrial morphology within genetic subsets of KRAS-mutant pancreatic cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.",
    "Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.",
    "University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.",
    "Department of Veterans Affairs, Veteran Affairs Medical Center, Cincinnati, OH, USA."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Grant A. Hagedorn",
      "orcid": "0000-0002-7238-7801"
    },
    {
      "affs": [
        0
      ],
      "name": "Jackson C. Spieser",
      "orcid": "0009-0009-5789-2605"
    },
    {
      "affs": [
        0
      ],
      "name": "Noriko Hirai",
      "orcid": "0000-0002-5175-0800"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuki Sato"
    },
    {
      "affs": [
        0
      ],
      "name": "Jake Valentine"
    },
    {
      "affs": [
        0
      ],
      "name": "Hanson Jiang",
      "orcid": "0009-0004-2116-9013"
    },
    {
      "affs": [
        1
      ],
      "name": "Wang Wang",
      "orcid": "0000-0001-9093-412X"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Maria F. Czyzyk-Krzeska",
      "orcid": "0000-0002-0693-8214"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Krushna C. Patra",
      "orcid": "0000-0002-2386-6435"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/brgt6nsd1npxm.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aeh7186",
  "fulltext_url": null,
  "id": "brgt6nsd1npxm",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aeh7186",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7214977668",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/brgt6nsd1npxm.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aeh7186",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aeh7186"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Mitochondrial Function and Pathology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gα s ) mutant pancreas cancer",
  "title_text": "Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gα s ) mutant pancreas cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/brgt6nsd1npxm",
  "venue": "Science Advances",
  "versions": []
}