Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer

Molecular Metabolism, Год журнала: 2022, Номер 60, С. 101469 - 101469

Опубликована: Март 10, 2022

The mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers neurodegenerative diseases. A range of structurally diverse small molecule inhibitors have been proposed, but the nature their interaction with MPC is not understood, composition functional human still debated. goal this study was to characterise protein in vitro, understand chemical features that determine binding develop novel higher affinity ones.

Язык: Английский

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Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult

Molecular Metabolism, Год журнала: 2023, Номер 77, С. 101808 - 101808

Опубликована: Сен. 15, 2023

Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As result, the mitochondrial carrier (MPC) complex has emerged as promising therapeutic target metabolic diseases. Clinical trials are currently underway. However, recent vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis toward glutaminolysis to compensate for loss of oxidation, possibly sensitizing cells oxidative insult. Here, we explored this vivo using clinically relevant acetaminophen (APAP) overdose model acute liver injury, which driven by stress. We used pharmacological genetic approaches inhibit MPC2 alanine aminotransferase 2 (ALT2), individually concomitantly, mice cell culture models determined effects on APAP hepatotoxicity. found sensitizes APAP-induced injury only with concomitant (ALT2). Pharmacological manipulation neither nor ALT2 alone affected toxicity, but liver-specific double knockout (DKO) significantly worsened damage. Further investigation indicated DKO impaired increased urea cycle flux, consistent glutaminolysis, these results were reproducible vitro. Finally, induction post-treatment dichloroacetate both reduced suggesting new avenues. Increased susceptibility toxicity requires vivo, indicating insufficient disrupt redox balance. Furthermore, suggest treatment

Язык: Английский

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A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma

Frontiers in Pharmacology, Год журнала: 2023, Номер 13

Опубликована: Янв. 10, 2023

Background: Cuproptosis is a newly discovered form of programmed cell death, which characterized by accumulation intra-cellular copper ion leading to the aggregation lipoproteins and destabilization Fe-S cluster proteins in mitochondrial metabolism, thereby affecting prognosis patients with cancer. However, role cuproptosis-related genes (CRGs) hepatocellular carcinoma (HCC) remains elusive. Methods: Mutation signature, copy number variation expression 10 CRGs were assessed HCC from TCGA-LIHC dataset. ICGC-LIRI-JP dataset was used as further validation cohort. The least absolute shrinkage selection operator (LASSO) construct prognostic model. Kaplan Meier curves, time-ROC nomogram, univariate multivariate Cox regression utilized evaluate predictive efficacy CRGs-score. Immune infiltration analyzed CIBERSOFT, ssGSEA algorithm, TIMER database. validated qPCR both in-vitro in-vivo. Drug sensitivity analysis performed pRRophetic. Results: All differentially expressed 5 out them (CDKN2A, DLAT, GLS, LIPT1, MTF1) correlated patient survival. These signature selected LASSO establish model stratify into high low CRGs-score subgroups. High associated worse prognosis. Subsequently, verified that an independent cancer risk factor clinical factors including stage grade. Nomogram integrating well predict revealed immune checkpoint significantly enhanced group, especially PD-1 PD-L1. An cohort (ICGC) confirmed stable universally applicable indicator predicting Concordantly, five also human lines mouse In addition, we targeted therapies between groups. Conclusion: This study elucidated dysregulated cohort, in-vivo models. might be applied novel HCC.

Язык: Английский

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Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma

JHEP Reports, Год журнала: 2024, Номер 6(5), С. 101077 - 101077

Опубликована: Март 27, 2024

The reprogramming of glutamine metabolism is a key event in cancers general, and hepatocellular carcinoma (HCC) particular. This supplies the tumor with ATP metabolites, through consumption which needed for anaplerosis tricarboxylic acid cycle (TCA). Alternatively, production can be enhanced an overexpression Glutamine Synthetase. In HCC, this specifically occurs activating mutations CTNNB1 gene coding β-catenin. Increased synthesis or use impacts epigenetics, oxidative stress, autophagy, immunity associated pathways such as mammalian target rapamycin (mTOR). review, we will discuss studies emphasize pro-tumoral suppressive effect overproduction. current state knowledge highlights need more comprehensive to evolve suitable targeted therapies would rely on metabolic pathways, depending predicted pro- anti-tumor role dysregulated occurring distinct genetic contexts.

Язык: Английский

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Protective effect of metformin on BPA-induced liver toxicity in rats through upregulation of cystathionine β synthase and cystathionine γ lyase expression

The Science of The Total Environment, Год журнала: 2020, Номер 750, С. 141685 - 141685

Опубликована: Авг. 12, 2020

Язык: Английский

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