ArticleMolecular cancer research : MCR2023
Mitochondrial Uncoupling Inhibits Reductive Carboxylation in Cancer Cells.
Article in Molecular cancer research : MCR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- CPT1A-mediated IDO1 succinylation shapes EGFRvIII-driven resistance to tumor electric field therapy in glioblastoma.Nature communications · 2026Article
- Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.Experimental hematology & oncology · 2026Review
- Review
- Nuclear receptor subfamily 4 group a member 2 induces a Warburg-like effect and promotes phospholipids synthesis in the mouse heart.Physiological genomics · 2026Article
- Mitochondrial uncoupling inhibits serine catabolismCancer biology & medicine · 2026Article
- Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition-Associated Toxicity.ACS medicinal chemistry letters · 2026Article
- Absolute quantification of TCA cycle intermediates in mouse ocular tissues reveals distinct tissue- and sex-specific mitochondrial metabolism.bioRxiv : the preprint server for biology · 2025Article
- Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Affinity-Based Protein Profiling Reveals IDH2 as a Mitochondrial Target of Cannabinol in Receptor-Independent Neuroprotection.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Mitochondrial glutamic-oxaloacetic transaminase (GOT2) in the growth of C2C12 myoblasts.Journal of bioenergetics and biomembranes · 2025Article
- Harnessing glycolysis in gastric cancer: molecular targets, therapeutic strategies, and clinical horizons.Frontiers in immunology · 2025Review
- The Warburg effect drives dedifferentiation through epigenetic reprogramming.Cancer biology & medicine · 2024Article
- Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state.Cell death & disease · 2024Article
- Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative tricarboxylic acid (TCA) cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth. IMPLICATIONS: Mitochondrial uncoupling is a novel strategy to target RC in cancer.
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