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Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
Wu, Zheng; Bezwada, Divya; Cai, Feng; Harris, Robert C; Ko, Bookyung; Sondhi, Varun; Pan, Chunxiao; Vu, Hieu S; Nguyen, Phong T; Faubert, Brandon; Cai, Ling; Chen, Hongli; Martin-Sandoval, Misty; Do, Duyen; Gu, Wen; Zhang, Yuanyuan; Zhang, Yuannyu; Brooks, Bailey; Kelekar, Sherwin; Zacharias, Lauren G; Oaxaca, K Celeste; Patricio, Joao S; Mathews, Thomas P; Garcia-Bermudez, Javier; Ni, Min; DeBerardinis, Ralph J.
Afiliación
  • Wu Z; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Bezwada D; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Cai F; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Harris RC; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Ko B; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Sondhi V; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Pan C; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Vu HS; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Nguyen PT; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Faubert B; Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • Cai L; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Can
  • Chen H; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Martin-Sandoval M; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Do D; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Gu W; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang Y; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang Y; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Brooks B; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Kelekar S; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zacharias LG; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Oaxaca KC; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Patricio JS; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Mathews TP; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Garcia-Bermudez J; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Ni M; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: min.ni@stjude.org.
  • DeBerardinis RJ; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ralph.deberardinis@utsouthwestern.edu.
Cell Metab ; 36(7): 1504-1520.e9, 2024 Jul 02.
Article en En | MEDLINE | ID: mdl-38876105
ABSTRACT
Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Mitocondrias Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Purinas / Mitocondrias Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos