Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol

Küch, Eva-Maria; Vellaramkalayil, Regina; Zhang, Ingrid W; Lehnen, Daniela; Brügger, Britta; Stremmel, Wolfgang; Ehehalt, Robert; Poppelreuther, Margarete; Füllekrug, Joachim

doi:10.1016/j.bbalip.2013.10.018

Cited by 119 publications

(97 citation statements)

References 83 publications

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“…Esterification of PUFA into phospholipids requires acyl-CoA synthase catalyzed formation of PUFA-CoA. Specifically, ACSL4 catalyzes synthesis of long-chain polyunsaturated-CoAs with a preference for AA 11 , thus facilitating their esterification into phospholipids 12 . While genetic ablation 13 or inhibition of ACSL4 by Triacsin C were both effective in protecting against RSL3 induced cell death (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

et al. 2016

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Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis - a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Here, by using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology we discovered that execution of ferroptosis involves a highly organized oxygenation center, whereby only one class of phospholipids, phosphatidylethanolamines (PE), undergoes oxidation in the ER-associated compartments with the specificity towards two fatty acyls – arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 acts as a specific anti-ferroptotic rescue pathway. Lipoxygenases (LOX) generate doubly- and triply-oxygenated (15-hydroperoxy)-di-acylated PE species which act as death signals while tocopherols and tocotrienols suppress LOX and protect against ferroptosis suggesting an unforeseen homeostatic physiological role of vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

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Section: Resultsmentioning

confidence: 99%

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

et al. 2016

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“…As for the ATB highly expressed groups (Supplementary Figure 2), 12 genes displayed an increased trend and were in agreement with the previous studies (Pacis et al, 2015) (Supplementary Table 4). Among which, ACSL4 and CLU were related with lipid metabolic process (Kuch et al, 2014; Park et al, 2014), and MMRN1 and POSTN were relevant to cell adhesion (Adam et al, 2005; Michaylira et al, 2010). These results suggested that the top-20 genes for each pattern might provide potential molecular targets for the prevention, diagnosis, and treatment of LTBI and ATB individuals.…”

Section: Resultsmentioning

confidence: 99%

RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Active and Latent Mycobacterium tuberculosis Infection

Zhang

et al. 2017

Front. Microbiol.

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Tuberculosis (TB) has exceeded HIV as the most lethal infectious disease globally for two consecutive years. Moreover, one third of the world’s population is estimated to have latent tuberculosis infection (LTBI). This is mainly because of difficulties associated with diagnosis and treatment for both TB and LTBI patients. Exosomes provide a promising research tool for TB diagnosis and treatment because they are released from various cells containing valuable biochemical information related to disease. In this study, we performed RNA-sequencing analysis on exosomes derived from clinical specimens of healthy controls (HC), active tuberculosis (ATB), and LTBI patients. Our results revealed the distinct gene expression profiles of the exosomes from LTBI and ATB patients. (1) We identified many distinct up-regulated and down-regulated differentially expressed genes (DEGs) in LTBI and ATB samples, and further screened the top-20 DEGs which might provide a potential panel for differentiation of HC, LTBI, and ATB. (2) We classified all the DEGs into six expression patterns, screened the top-20 genes in each pattern, and mainly focused on those highly expressed in LTBI and ATB. (3) Some Mycobacterium tuberculosis (Mtb) RNAs were only enriched in the exosomes of LTBI samples. (4) Pathway and function analysis further indicated down-regulated signaling pathways/immune response and up-regulated apoptosis/necrosis. Our findings indicate the selective packaging of RNA cargoes into exosomes under different stages of Mtb infection, while facilitating the development of potential targets for the diagnosis, prevention and treatment of tuberculosis.

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“…Thus, ACSLs and ACSs designated as FA transport proteins (FATPs) enhance FA uptake even when they are located on intracellular membranes (22). An example is provided by similar uptake of arachidonate by each of two differentially spliced variants of ACSL4, one located on the plasma membrane and in the cytosol and the other located on the ER and lipid droplets (23). Overexpressing ACSL4 at the ER generated 50% more phosphatidylinositol than when it was targeted to the mitochondria, compatible with a specific interaction with ER enzymes that synthesize or remodel phosphatidylinositol.…”

Section: Vectorial Acylationmentioning

confidence: 96%

Physiological Consequences of Compartmentalized Acyl-CoA Metabolism

Cooper

Young

Klett

et al. 2015

Journal of Biological Chemistry

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Meeting the complex physiological demands of mammalian life requires strict control of the metabolism of long-chain fatty acyl-CoAs because of the multiplicity of their cellular functions. Acyl-CoAs are substrates for energy production; stored within lipid droplets as triacylglycerol, cholesterol esters, and retinol esters; esterified to form membrane phospholipids; or used to activate transcriptional and signaling pathways. Indirect evidence suggests that acyl-CoAs do not wander freely within cells, but instead, are channeled into specific pathways. In this review, we will discuss the evidence for acyl-CoA compartmentalization, highlight the key modes of acyl-CoA regulation, and diagram potential mechanisms for controlling acylCoA partitioning.Two prevailing views of metabolic pathways within the cytosol are a) as sequential steps within a largely empty space with substrates and products traveling from one enzyme to the next, and b), as embedded within a dense network of proteins and metabolites, all jockeying for position. In contrast to these two views, it is likely that synthetic and degradative pathways are composed of enzymes and their regulators in highly organized multi-enzyme assemblies designed to enhance efficiency and regulate steady-state flux (1). Proteins within these assemblies might interact via their transmembrane and extra-membrane domains or be tethered to scaffolds, in a manner that is regulated by allosteric effectors and post-translational modifications (2, 3). Such interactions may be transient, as occurs with the enzymes that comprise purinosomes (4), or they may be semi-permanent as occurs within glycogen granules that contain enzymes that synthesize and degrade glycogen, and their regulatory kinases and phosphatases (5, 6). Assemblies of proteins are advantageous because even without a physical tunnel, they can increase reaction rates by enhancing local substrate concentrations, restricting intermediates from entering competing reactions, and stabilizing chemically unstable intermediates.Because the dysregulation of metabolic homeostasis has been implicated in a multitude of human diseases, acyl-CoA metabolism represents a critical node for understanding whole-body pathophysiology. Apart from eicosanoid synthesis, the first step in the metabolism of long-chain fatty acids (FAs) 2 is their thioesterification. The resulting acyl-CoA is then metabolized by one of six major enzyme families: elongases and desaturases (7), dehydrogenases (8, 9), acyl-CoA thioesterases (10, 11), carnitine palmitoyltransferases (CPT) (12), and lipid and protein acyltransferases (13) (Fig. 1). These competing pathways, often present within a single subcellular compartment and coupled with the highly specialized metabolism of individual cells and tissues, suggest a level of organization extending beyond enzymatic function. In this review, we will use a physiological lens to focus on longchain mammalian fatty acyl-CoAs and the evidence for compartmentalized acyl-CoA metabolism.

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Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol

Cited by 119 publications

References 83 publications

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

RNA Profiling Analysis of the Serum Exosomes Derived from Patients with Active and Latent Mycobacterium tuberculosis Infection

Physiological Consequences of Compartmentalized Acyl-CoA Metabolism

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