Cancer cell metabolism: Rewiring the mitochondrial hub

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2020, Volume and Issue: 1867(2), P. 166016 - 166016

Published: Nov. 25, 2020

Language: Английский

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Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis

Biochemical Pharmacology, Journal Year: 2022, Volume and Issue: 198, P. 114943 - 114943

Published: Feb. 5, 2022

Language: Английский

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Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(4)

Published: June 27, 2023

Abstract The mitochondrial pyruvate carrier (MPC) resides in the inner membrane, where it links cytosolic and metabolism by transporting produced glycolysis into matrix. Due to its central metabolic role, has been proposed as a potential drug target for diabetes, non‐alcoholic fatty liver disease, neurodegeneration, cancers relying on metabolism. Little is known about structure mechanism of MPC, proteins involved were only identified decade ago technical difficulties concerning their purification stability have hindered progress functional structural analyses. unit MPC hetero‐dimer comprising two small homologous membrane proteins, MPC1/MPC2 humans, with alternative complex MPC1L/MPC2 forming testis, but are found throughout tree life. predicted topology each protomer consists an amphipathic helix followed three transmembrane helices. An increasing number inhibitors being identified, expanding pharmacology providing insights inhibitory mechanism. Here, we provide critical composition, structure, function summarize different classes molecule therapeutics.

Language: Английский

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Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(12), P. 1821 - 1832

Published: Dec. 1, 2023

Abstract Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes well known to drive lineage transitions, it remains unclear how upstream metabolic signalling contributes the regulation epithelial identity. To fill this gap, we developed an approach perform metabolomics on primary cells. Using approach, discovered that basal luminal cells exhibit distinct metabolomes nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish mitochondrial carrier subsequent lactate accumulation as regulators Inhibition or supplementation with exogenous results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors response antiandrogen treatment. These reciprocal metabolism

Language: 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, Journal Year: 2023, Volume and Issue: 77, P. 101808 - 101808

Published: Sept. 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

Language: Английский

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Blocking mitochondrial pyruvate import in brown adipocytes induces energy wasting via lipid cycling

EMBO Reports, Journal Year: 2020, Volume and Issue: 21(12)

Published: Dec. 3, 2020

Abstract Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP‐consuming process that contributes to energy expenditure. Therefore, interventions stimulate expenditure through cycling are of great interest. Here we find pharmacological genetic inhibition the mitochondrial pyruvate carrier (MPC) in brown adipocytes activates expenditure, even absence adrenergic stimulation. We show resulting increase ATP demand elevates respiration coupled synthesis fueled by oxidation. identify glutamine consumption Malate‐Aspartate Shuttle required for Energy Expenditure induced MPC Brown Adipocytes (MAShEEBA). thus demonstrate enhanced can be activated decreasing availability. present a new mechanism fat oxidation adipocytes, which does not require stimulation uncoupling.

Language: Английский

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Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease

Journal of Internal Medicine, Journal Year: 2020, Volume and Issue: 289(1), P. 84 - 96

Published: July 7, 2020

The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence complex molecular processes. Mitochondrial dysfunction a hallmark feature advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), member oxidative phosphorylation system, key component respirasome supercomplex. Here, we hypothesized that NAFLD severity associated with tissue b mutations and damaged mitochondrial DNA (mtDNA).We included 252 specimens patients in whom ranged from mild to which were linked clinical biochemical information. Tissue explorations MT-CYB sequencing analysis differential mtDNA damage. Profiling circulating Krebs cycle metabolites global transcriptome was performed subsample patients. levels 4-hydroxynonenal product lipid peroxidation 8-hydroxy-2'-deoxyguanosine, marker damage measured.Compared simple steatosis, NASH higher level variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). burden variants increased 2-hydroxyglutarate, branched-chain amino acids, glutamate, changes transcriptome. Liver inflammation. adducts peroxyl radicals.NASH genetic alterations cellular respirasome, including high variation damage, may result broad effects.

Language: Английский

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Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(8), P. 4173 - 4173

Published: April 17, 2021

Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver and third-leading cause cancer-related mortality. Currently, global burden nonalcoholic fatty disease (NAFLD) has dramatically overcome both viral alcohol hepatitis, thus becoming main HCC incidence. NAFLD pathogenesis severely influenced by lifestyle genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics epigenetics (“mitochondrial plasticity”). Mounting evidence highlights mitochondrial dysfunction due loss flexibility arise before overt NAFLD, from early stages injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation fibrosis, generating an adverse microenvironment several hepatocytes select anti-apoptotic programs mutations allow survival proliferation. Furthermore, one key events malignant represented remodeling glucidic–lipidic metabolism combined with reprogramming functions, optimized deal energy demand. In sum, this review will discuss how defects be translated into causative explanations NAFLD-driven HCC, emphasizing future directions for research development potential preventive or curative strategies.

Language: Английский

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Interrogating in vivo T-cell metabolism in mice using stable isotope labeling metabolomics and rapid cell sorting

Nature Protocols, Journal Year: 2021, Volume and Issue: 16(9), P. 4494 - 4521

Published: Aug. 4, 2021

Language: Английский

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

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 60, P. 101469 - 101469

Published: March 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.

Language: Английский

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