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Adv."],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>G12D<\/jats:sup>\n                    and\n                    <jats:italic toggle=\"yes\">GNAS<\/jats:italic>\n                    complex locus gene (GNAS\n                    <jats:sup>R201C\/H<\/jats:sup>\n                    ) mutations, we found that despite the presence of mutant Kras, hyperactive Gnas\n                    <jats:sup>R201C<\/jats:sup>\n                    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\n                    <jats:sup>R201C<\/jats:sup>\n                    -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\n                    <jats:sup>+<\/jats:sup>\n                    ) metabolites to promote mitochondrial elongation. NAD\n                    <jats:sup>+<\/jats:sup>\n                    availability is crucial for mitochondrial fusion, as facilitating NAD\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh7186","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:26Z","timestamp":1790791106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in\n                    <i>GNAS<\/i>\n                    (G\u03b1\n                    <sub>s<\/sub>\n                    ) mutant pancreas cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-7801","authenticated-orcid":true,"given":"Grant 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