Electron transport chain inhibition increases cellular dependence on purine transport and salvage.

HPRT1 NAD(+):NADH ratio electron transport chain metabolomics purine metabolism stable isotopes

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
07 Jun 2024
Historique:
received: 02 05 2023
revised: 11 03 2024
accepted: 22 05 2024
medline: 15 6 2024
pubmed: 15 6 2024
entrez: 14 6 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.cmet.2024.05.014 PMID: 38876105
pubmed: 38876105
pii: S1550-4131(24)00190-6
doi: 10.1016/j.cmet.2024.05.014
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests R.J.D. is a founder at Atavistik Bio and serves on the Scientific Advisory Boards of Atavistik Bio, Agios Pharmaceuticals, Faeth Therapeutics, General Metabolics, and Vida Ventures.

Auteurs

Zheng Wu (Z)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Divya Bezwada (D)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Feng Cai (F)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Robert C Harris (RC)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Bookyung Ko (B)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Varun 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.

Chunxiao Pan (C)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Hieu S Vu (HS)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Phong T Nguyen (PT)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Brandon Faubert (B)

Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

Ling 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 Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Hongli Chen (H)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Misty Martin-Sandoval (M)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Duyen Do (D)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Wen Gu (W)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Yuanyuan 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.

Yuannyu Zhang (Y)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Bailey Brooks (B)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Sherwin Kelekar (S)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Lauren G Zacharias (LG)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

K Celeste Oaxaca (KC)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Joao S Patricio (JS)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Thomas P Mathews (TP)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Javier Garcia-Bermudez (J)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Min Ni (M)

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: min.ni@stjude.org.

Ralph J 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.

Classifications MeSH