Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gα s ) mutant pancreas cancer
4 affiliations
- 1Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- 2Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
- 3University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- 4Department of Veterans Affairs, Veteran Affairs Medical Center, Cincinnati, OH, USA.
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.
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BibTeX
@article{hagedorn2026remodeling,
title = {{Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gα s ) mutant pancreas cancer}},
author = {Grant A. Hagedorn and Jackson C. Spieser and Noriko Hirai and Yuki Sato and Jake Valentine and Hanson Jiang and Wang Wang and Maria F. Czyzyk-Krzeska and Krushna C. Patra},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh7186},
url = {https://www.science.org/doi/10.1126/sciadv.aeh7186},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Remodeling of mitochondrial dynamics by metabolic pathways couples to oncogenic growth in GNAS (Gα s ) mutant pancreas cancer
AU - Grant A. Hagedorn
AU - Jackson C. Spieser
AU - Noriko Hirai
AU - Yuki Sato
AU - Jake Valentine
AU - Hanson Jiang
AU - Wang Wang
AU - Maria F. Czyzyk-Krzeska
AU - Krushna C. Patra
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aeh7186
UR - https://www.science.org/doi/10.1126/sciadv.aeh7186
AB - 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.
SN - 2375-2548
ER -