FDX1 regulates cellular protein lipoylation through direct binding to LIAS

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(9), С. 105046 - 105046

Опубликована: Июль 13, 2023

Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes conserved through evolution. The promiscuous nature ferredoxins enables them to participate many metabolic including steroid, heme, vitamin D, and Fe-S biosynthesis different organisms. However, the unique natural function(s) each two human (FDX1 FDX2) still poorly characterized. We recently reported FDX1 is both crucial regulator copper ionophore-induced cell death serves an upstream protein lipoylation, mitochondrial lipid-based post-translational modification naturally occurring on four enzymes for TCA cycle function. Here we show directly regulates lipoylation by binding lipoyl synthase (LIAS) enzyme promoting its functional carrier GCSH not indirect regulation biosynthesis. Metabolite profiling revealed predominant outcome loss function manifested lipoylation-dependent ultimately resulting respiration sensitivity mild glucose starvation. Transcriptional established loss-of-function results induction compensatory metabolism-related genes integrated stress response, consistent with our findings conditionally lethal. Together, establish engages LIAS, role process maintaining viability under low conditions.

Язык: Английский

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Cuproptosis and cuproptosis-related genes: Emerging potential therapeutic targets in breast cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1878(6), С. 189013 - 189013

Опубликована: Окт. 31, 2023

Язык: Английский

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Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(9), С. 105075 - 105075

Опубликована: Июль 20, 2023

Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins ferredoxin (FDX) family of carriers. Humans have two FDXs- FDX1 FDX2, both which localized to mitochondria, latter is itself important for ISC synthesis. We previously shown hypoxia can eliminate requirement some components biosynthetic pathway, but FDXs were not included study. Here, we report FDX1, dispensable under 1% O

Язык: Английский

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FDX1 regulates cellular protein lipoylation through direct binding to LIAS

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Фев. 4, 2023

Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes conserved through evolution. The promiscuous nature ferredoxins enables them to participate many metabolic including steroid, heme, vitamin D and Fe-S biosynthesis different organisms. However, the unique natural function(s) each two human (FDX1 FDX2) still poorly characterized. We recently reported FDX1 is both crucial regulator copper ionophore induced cell death serves an upstream protein lipoylation, mitochondrial lipid-based post translational modification naturally occurring on four enzymes for TCA cycle function. Here we show regulates lipoylation by directly binding lipoyl synthase (LIAS) enzyme not indirect regulation biosynthesis. Metabolite profiling revealed predominant outcome loss-of-function manifested lipoylation-dependent ultimately resulting loss respiration sensitivity mild glucose starvation. Transcriptional cells growing either normal or low conditions established results induction compensatory metabolism related genes integrated stress response, consistent with our findings loss-of-functions conditionally lethal. Together, establish engages LIAS, promoting process maintaining viability under conditions.

Язык: Английский

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Epilepsy: Mitochondrial connections to the ‘Sacred’ disease

Mitochondrion, Год журнала: 2023, Номер 72, С. 84 - 101

Опубликована: Авг. 13, 2023

Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms epilepsy makes diagnosis challenging. Diagnosis and monitoring childhood add to the need non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms epileptogenesis are not fully understood, evidence mitochondrial involvement is substantial. Seizures affect 35%-60% patients diagnosed with diseases. Mitochondrial dysfunction pathophysiological in various epilepsies, including those non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads altered neuronal bioenergetics, metabolism neurological complications, Iron-dependent lipid peroxidation initiates ferroptosis, a death pathway that aligns morphology found neurodegenerative diseases (NDDs). Studies mouse genetic models seizure phenotypes where function an essential selenoprotein (GPX4) targeted suggest roles ferroptosis epilepsy. GPX4 pivotal NDDs, selenium protects interneurons ferroptosis. Selenium central nervous system micronutrient trace element. Low serum concentrations other elements minerals, iron, noted diagnosing supplements alleviate intractable seizures children reduced GPX activity. Copper cuproptosis, like iron link NDDs. Connecting these mechanistic pathways selenoproteins provides new insights into treating seizures, pointing using medicines prodrugs lipoic acid treat potential alternative therapeutic approaches transcranial magnetic stimulation (transcranial), photobiomodulation vagus nerve stimulation.

Язык: Английский

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The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism

Redox Biology, Год журнала: 2024, Номер 72, С. 103155 - 103155

Опубликована: Апрель 10, 2024

The α-keto acid dehydrogenase complex (KDHc) class of mitochondrial enzymes is composed four members: pyruvate (PDHc), α-ketoglutarate (KGDHc), branched-chain keto (BCKDHc), and 2-oxoadipate (OADHc). These enzyme complexes occupy critical metabolic intersections that connect monosaccharide, amino acid, fatty metabolism to Krebs cycle flux oxidative phosphorylation (OxPhos). This feature also imbues KDHc with the heightened capacity serve as platforms for propagation intracellular intercellular signaling. a source sink hydrogen peroxide (mtH2O2), vital second messenger used trigger eustress pathways. Notably, deactivation through reversible oxidation by mtH2O2 other electrophiles modulates availability several intermediates related metabolites which powerful messengers. play important roles in modulation epigenetic programming nucleus provision various acyl-CoAs, are acylate proteinaceous lysine residues. nucleosomal control acylation achieved PDHc KGDHc localization nuclear lumen. In this review, I discuss emerging concepts signaling fulfilled complexes. highlight their function serving redox sensors how can be cells regulate required cell Coupled this, describe detail defects cause disease states disruption homeodynamics deregulation Finally, propose functions controlled modification vicinal lipoic thiols E2 subunit

Язык: Английский

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Twenty Years of Radical SAM! The Genesis of the Superfamily

ACS Bio & Med Chem Au, Год журнала: 2022, Номер 2(6), С. 538 - 547

Опубликована: Дек. 5, 2022

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTTwenty Years of Radical SAM! The Genesis the SuperfamilySquire J. Booker*Squire BookerDepartments Chemistry, Biochemistry and Molecular Biology Howard Hughes Medical Institute, , Pennsylvania State University, University Park, 16802, United StatesMore by Squire Bookerhttps://orcid.org/0000-0002-7211-5937 Cody T. LloydCody LloydBiochemistry Biology, Lloydhttps://orcid.org/0000-0003-2392-126XCite this: ACS Bio Med Chem Au 2022, 2, 6, 538–547Publication Date (Web):December 5, 2022Publication History Received21 November 2022Published online5 December inissue 21 2022https://doi.org/10.1021/acsbiomedchemau.2c00078Copyright © Published 2022 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceCC: Creative CommonsBY: Credit must be given to creatorNC: Only noncommercial uses work are permittedND: No derivatives or adaptations permittedArticle Views757Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views COUNTER-compliant sum full text article downloads since 2008 (both PDF HTML) across all institutions individuals. These metrics regularly updated reflect usage leading up last few days.Citations number other articles citing this article, calculated Crossref daily. Find more information about citation counts.The Altmetric Attention Score is a quantitative measure attention that research has received online. Clicking on donut icon will load page at altmetric.com with additional details score social media presence for article. how calculated. Share Add toView InAdd Full Text ReferenceAdd Description ExportRISCitationCitation abstractCitation referencesMore Options onFacebookTwitterWechatLinked InReddit (5 MB) Get e-AlertsSUBJECTS:Bacteria,Biosynthesis,Cluster chemistry,Peptides proteins,Sulfur e-Alerts

Язык: Английский

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MACAW: a method for semi-automatic detection of errors in genome-scale metabolic models

Genome biology, Год журнала: 2025, Номер 26(1)

Опубликована: Март 28, 2025

Genome-scale metabolic models (GSMMs) are used to predict fluxes, with applications ranging from identifying novel drug targets engineering microbial metabolism. Erroneous or missing reactions, scattered throughout densely interconnected networks, a limiting factor in these applications. We present Metabolic Accuracy Check and Analysis Workflow (MACAW), suite of algorithms that helps identify visualize errors at the level connected pathways, rather than individual reactions. show how MACAW highlights inaccuracies varying severity manually curated automatically generated GSMMs for humans, yeast, bacteria systematic issues be addressed future model construction efforts.

Язык: Английский

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Lipoic acid attachment to proteins: stimulating new developments

Microbiology and Molecular Biology Reviews, Год журнала: 2024, Номер 88(2)

Опубликована: Апрель 16, 2024

SUMMARYLipoic acid-modified proteins are essential for central metabolism and pathogenesis. In recent years, the

Язык: Английский

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Assembly, transfer, and fate of mitochondrial iron–sulfur clusters

Journal of Experimental Botany, Год журнала: 2023, Номер 74(11), С. 3328 - 3344

Опубликована: Фев. 27, 2023

Abstract Since the discovery of an autonomous iron–sulfur cluster (Fe–S) assembly machinery in mitochondria, significant efforts to examine nature this process have been made. The Fe–S clusters occurs two distinct steps with initial synthesis [2Fe–2S] by a first followed subsequent into [4Fe–4S] second machinery. Despite knowledge, we still only rudimentary understanding how are transferred and distributed among their respective apoproteins. In particular, demand created continuous protein turnover sacrificial destruction for biotin lipoic acid reveal possible bottlenecks supply chain clusters. Taking available information from other species consideration, review explores mitochondrial Arabidopsis provides current knowledge about transfer Furthermore, highlights synthase lipoyl synthase, which both utilize as sulfur source. After extraction atoms these clusters, remains probably fall apart, releasing sulfide highly toxic by-product. Immediate refixation through local cysteine biosynthesis is therefore essential salvage pathway emphasizes physiological need plant mitochondria.

Язык: Английский

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