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Updated: Jan 20, 2026
Synthesis and Evaluation of a Ruthenium-based Mitochondrial Calcium Uptake Inhibitor
Published on: October 26, 2017
Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and
Sean C Tompkins1, Ryan D Sheldon1, Adam J Rauckhorst1
1Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Abstract:
Hepatocellular carcinoma (HCC) is a devastating cancer increasingly caused by non-alcoholic fatty liver disease (NAFLD). Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) in mice attenuates NAFLD. Thus, we considered whether liver MPC disruption also prevents HCC. Here, we use the N-nitrosodiethylamine plus carbon tetrachloride model of HCC development to test how liver-specific MPC knock out affects hepatocellular tumorigenesis. Our data show that liver MPC ablation markedly decreases tumorigenesis and that MPC-deficient tumors transcriptomically downregulate glutathione metabolism. We observe that MPC disruption and glutathione depletion in cultured hepatomas are synthetically lethal. Stable isotope tracing shows that hepatocyte MPC disruption reroutes glutamine from glutathione synthesis into the tricarboxylic acid (TCA) cycle. These results support a model where inducing metabolic competition for glutamine by MPC disruption impairs hepatocellular tumorigenesis by limiting glutathione synthesis. These findings raise the possibility that combining MPC disruption and glutathione stress may be therapeutically useful in HCC and additional cancers.
Insights
Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) reduces liver cancer (HCC) development by limiting glutathione synthesis. This metabolic strategy may offer new therapeutic avenues for HCC and other cancers.
Area of Science:
- Hepatology
- Oncology
- Cancer Metabolism
Background:
- Hepatocellular carcinoma (HCC) is a significant health concern, often linked to non-alcoholic fatty liver disease (NAFLD).
- Previous research indicated that disrupting the liver Mitochondrial Pyruvate Carrier (MPC) can mitigate NAFLD in mouse models.
Purpose of the Study:
- To investigate the effect of liver-specific MPC disruption on the development of hepatocellular carcinoma (HCC).
Main Methods:
- Utilized the N-nitrosodiethylamine plus carbon tetrachloride mouse model to induce HCC.
- Performed liver-specific MPC knockout in mice.
- Analyzed tumor development and gene expression.
- Conducted metabolic tracing studies using stable isotopes in cultured hepatomas.
Main Results:
- Liver-specific MPC ablation significantly reduced hepatocellular tumorigenesis.
- MPC-deficient tumors exhibited downregulated glutathione metabolism.
- MPC disruption and glutathione depletion showed synthetic lethality in cultured hepatomas.
- Hepatocyte MPC disruption redirected glutamine from glutathione synthesis to the TCA cycle.
Conclusions:
- MPC disruption induces metabolic competition for glutamine, impairing HCC development by limiting glutathione synthesis.
- Combining MPC disruption with glutathione stress presents a potential therapeutic strategy for HCC and other cancers.
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