Getting out what you put in: Copper in mitochondria and its impacts on human disease

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2020, Volume and Issue: 1868(1), P. 118867 - 118867

Published: Oct. 2, 2020

Language: Английский

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Harnessing metabolic dependencies in pancreatic cancers

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 18(7), P. 482 - 492

Published: March 19, 2021

Language: Английский

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Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

Molecular Metabolism, Journal Year: 2022, Volume and Issue: 60, P. 101481 - 101481

Published: March 25, 2022

Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability eukaryotic cells precisely regulate their biochemical functions. Membrane-bound such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable concentration precursors optimized chemical environments, greatly accelerating efficiency both anabolic catabolic reactions, enabling division labor optimal utilization resources. However, also poses a challenge because it creates spatial discontinuities that must be bridged for reaction cascades connected completed. To do so, employ different methods coordinate fluxes occurring in organelles, membrane-localized transporters facilitate regulated metabolite exchange between mitochondria lysosomes, non-vesicular transport via physical contact sites connecting ER with well localized regulatory signaling processes coordinately activity all these organelles.

Language: Английский

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Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 5, 2022

Abstract The SLC25 carrier family consists of 53 transporters that shuttle nutrients and co-factors across mitochondrial membranes. is highly redundant their transport activities coupled to metabolic state. Here, we use a pooled, dual CRISPR screening strategy knocks out pairs in four states — glucose, galactose, OXPHOS inhibition, absence pyruvate designed unmask the inter-dependence these genes. In total, screen 63 genes states, corresponding 2016 single pair-wise genetic perturbations. We recover 19 gene-by-environment (GxE) interactions 9 gene-by-gene (GxG) interactions. One GxE interaction hit illustrates fitness defect folate (SLC25A32) KO cells genetically buffered galactose due lack substrate de novo purine biosynthesis. GxG analysis highlights buffering between iron transporter SLC25A37 (A37) poorly characterized SLC25A39 (A39). Mitochondrial metabolite profiling, organelle assays, structure-guided mutagenesis identify A39 as critical for glutathione (GSH) import. Functional studies reveal A39-mediated homeostasis A37-mediated uptake operate jointly support OXPHOS. Our work underscores value studying family-wide different environments.

Language: Английский

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The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Oct. 14, 2022

The mechanism of cuproptosis has recently been reported in lipoylated proteins the tricarboxylic acid (TCA) cycle. Besides, role copper was previously recognized cancer progression. We evaluated prognostic value cuproptosis-related gene expression hepatocellular carcinoma (HCC). Remarkable genes were selected both differential analysis and Kaplan-Meier survival from ninety-six using Cancer Genome Atlas (TCGA) database. relationships between clinical characteristics performed with Wilcoxon signed-rank test, Kruskal-Wallis logistic regression. Clinicopathologic factors correlated overall HCCs conducting univariate multivariate Cox regression analysis. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) Human Protein (HPA) databases utilized to verify results. Furthermore, Set Enrichment (GSEA) identified potential key pathways that dominate HCC. Elevated ATP7A, SLC25A3, SCO2, COA6, TMEM199, ATP6AP1, LIPT1, DLAT, PDHA1, MTF1, ACP1, FDX2, NUBP2, CIAPIN1, ISCA2 NDOR1 expression, as well declined AOC1, FDX1, MT-CO1, ACO1 significantly emerged HCC tumor tissues associated poor survival. expressions screened prominently related features. GSEA many signaling (such natural killer cell mediated cytotoxicity, TCA cycle, glutathione metabolism, ATP-binding cassette (ABC) transporters, Notch pathway, ErbB metabolism xenobiotics by cytochrome p450) differentially enriched varying degrees expression. twenty might be new candidate biomarkers for

Language: Английский

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Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes

Cell Reports, Journal Year: 2023, Volume and Issue: 42(6), P. 112641 - 112641

Published: June 1, 2023

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis reduced in mice deficient of Ppm1k, a positive regulator BCAA catabolism, which protects against obesity-induced intolerance. Accumulation branched-chain keto acids (BCKAs) inhibits production hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported selectively suppressed Ppm1k-deficient can be restored with pharmacological activation BCKA catabolism by BT2. Finally, hepatocytes lack aminotransferase alleviates accumulation via reversible conversion between BCAAs BCKAs. This renders MPC most susceptible circulating levels hence sensor catabolism.

Language: Английский

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The crosstalk between mitochondrial quality control and metal-dependent cell death

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(4)

Published: April 27, 2024

Abstract Mitochondria are the centers of energy and material metabolism, they also serve as storage dispatch hubs metal ions. Damage to mitochondrial structure function can cause abnormal levels distribution ions, leading cell dysfunction even death. For a long time, quality control pathways such dynamics mitophagy have been considered inhibit metal-induced However, with discovery new metal-dependent death including ferroptosis cuproptosis, increasing evidence shows that there is complex relationship between This article reviews latest research results mechanisms crosstalk in recent years, well their involvement neurodegenerative diseases, tumors other order provide ideas for treatment related diseases.

Language: Английский

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Tumor bud-derived CCL5 recruits fibroblasts and promotes colorectal cancer progression via CCR5-SLC25A24 signaling

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: March 3, 2022

Tumor budding is included in the routine diagnosis of colorectal cancer (CRC) and considered a tumor prognostic factor independent TNM staging. This study aimed to identify fibroblast-mediated effect bud-derived C-C chemokine ligand 5 (CCL5) on microenvironment (TME).Recruitment assays human cytokine array were used detect main cytokines that CRC buds secrete recruit fibroblasts. siRNA transfection inhibitor treatment investigate role fibroblast CCL5 receptors recruitment. Subsequently, transcriptome sequencing was performed explore molecular changes occurring fibroblasts upon stimulation with CCL5. Finally, clinical specimens orthotopic xenograft mouse models studied contribution angiogenesis collagen synthesis.Hematoxylin-eosin staining immunochemistry revealed higher number at invasive front tissue showing than sites without budding. In vitro experiments demonstrated derived from could by acting CCR5 also positively regulate solute carrier family 25 member 24 (SLC25A24) expression fibroblasts, potentially activating pAkt-pmTOR signaling. Moreover, increase α-SMAhigh CD90high FAPlow thus promote enhancing VEGFA making transdifferentiate into vascular endothelial cells. results showed synthesis through contributing progression.At CRC, can via CCR5-SLC25A24 signaling, further promoting recruited eventually create tumor-promoting microenvironment. Therefore, may serve as potential diagnostic marker therapeutic target for CRC.

Language: Английский

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Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(4), P. 802 - 810.e6

Published: Dec. 28, 2023

Language: Английский

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Biogenesis of Mitochondrial Metabolite Carriers

Biomolecules, Journal Year: 2020, Volume and Issue: 10(7), P. 1008 - 1008

Published: July 7, 2020

Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize majority ATP. Like almost all proteins, have to be imported into from cytosol. Carrier precursors utilize a specialized translocation pathway dedicated biogenesis related carrier translocase (TIM22) pathway. After recognition import through outer via (TOM) complex, ushered intermembrane space by hexameric TIM chaperones ultimately integrated TIM22 translocase. Recent advances shed light on mechanisms TOM chaperone function, uncovered an unexpected versatility machineries, revealed novel components functional crosstalk human

Language: Английский

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