Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

Brüning, Ulrike; Morales-Rodriguez, Francisco; Kalucka, Joanna; Goveia, Jermaine; Taverna, Federico; Queiroz, Karla; Dubois, Charlotte; Cantelmo, Anna Rita; Chen, Rongyuan; Loroch, Stefan; Timmerman, Evy; Caixeta, Vanessa; Bloch, Katarzyna; Conradi, Lena‐Christin; Treps, Lucas; Staes, An; Gevaert, Kris; Tee, Andrew R.; Dewerchin, Mieke; Semenkovich, Clay F.; Impens, Francis; Schilling, Birgit; Verdin, Eric; Swinnen, Johannes V.; Meier, Jordan L.; Kulkarni, Rhushikesh A.; Sickmann, Albert; Ghesquière, Bart; Schoonjans, Luc; Li, Xuri; Mazzone, Massimiliano; Carmeliet, Peter

doi:10.1016/j.cmet.2018.07.019

Cited by 179 publications

(152 citation statements)

References 58 publications

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“…This underlines the crucial role of citrate for proliferating HUVECs metabolism in need of phospholipids to build up new lipid bilayers ( Figure 6 ) [ 3 ]. Disruption of fatty acid synthesis was actually shown to reduce ECs proliferation and impair angiogenesis [ 3 , 25 ]. Of note, the deficit in glutamate availability is also very likely to influence non-mitochondrial pathways such as the glutathione and proline synthesis that we found to be completely inhibited in the presence of BPTES.…”

Section: Discussionmentioning

confidence: 99%

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Schoonjans

Mathieu

Joudiou

et al. 2020

JCM

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Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.

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Section: Discussionmentioning

confidence: 99%

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Schoonjans

Mathieu

Joudiou

et al. 2020

JCM

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“…Moreover, FA synthase (FASN), an enzyme consuming malonyl-CoA, reduces the level of malonyl-CoA, which in turn decreases mTOR (K1218) malonylation. Malonylation impairs mTORC1 kinase activity, eventually leads to angiogenic defects, an event involved in MI [115]. Therefore, protein malonylation is critically involved in cardiac and vascular physiological and pathological processes.…”

Section: Malonate and Malonylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

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“…Malonylation of mTOR reduces mTORC1 complex activity, decreasing endothelial cell proliferation and reducing angiogenesis in a human umbilical model 44 . Together these studies and others suggest a potentially pervasive role for mal-CoA in sensing and responding to nutritional status.…”

Section: Discussionmentioning

confidence: 97%

Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis inCaenorhabditis elegans

Starich

Greenstein

2020

Preprint

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Gap junctions are virtually ubiquitous in metazoans and play critical roles in many important biological processes, including electrical conduction and development. Despite this ubiquity, only a small number of molecules passing through gap junction channels have been definitively linked to specific functions.We isolated gap junction channel mutants that reduce junctional coupling between the soma and germ cells in the C. elegans gonad. We use genetic methods to show that malonyl-CoA, the rate-limiting substrate for fatty acid synthesis (FAS), is produced in the soma and delivered through gap junctions to the germline; there it is used by fatty acid synthase to critically support embryonic development. Tissue separation of malonyl-CoA production from its site of utilization facilitates somatic control of germline development and reproduction.Further, our results suggest that this metabolic outsourcing may be a strategy by which the soma communicates nutritional status to the germline.Gap junctions are clusters of intercellular channels allowing direct passage of small molecules between coupled cells. They are widespread in multicellular organisms, though different gene families encode the protein subunits in invertebrates (innexins) and vertebrates (primarily connexins) 1 . While the capability of small molecules to pass through gap junctions can be shown readily in cultured cells, identification of essential molecules that must pass through channels in vivo is challenging. Additionally, disruption of gap junction coupling can affect cell adhesion 2 , and resultant defects in intercellular communication may not necessarily relate to the passage of molecules through junctional channels.In C. elegans, germ cells are coupled throughout their development to the somatic gonad by gap junctions 3 . Germ cells progress in assembly-line fashion through the early stages of meiosis (Fig. 1a). Gonadal gap junctions have been implicated in germ cell proliferation, oocyte growth, regulation of oocyte meiotic maturation, early embryogenesis and sperm guidance 3-7 . Gap junction hemichannels (half-channels) in the somatic gonad are comprised of the recently duplicated innexins INX-8 and INX-9; apposing germ cell hemichannels are heteromeric and consist of INX-14 in conjunction with either INX-21 or INX-22 ( Supplementary Fig. 1). Germ cells fail to proliferate in inx-8(0) inx-9(0) mutants, at a point upstream of, or parallel to, GLP-1/Notch activation of germ cells by Delta class ligands LAG-2 and APX-1. These ligands are produced in the distal tip cell (DTC) that maintains the proliferative stem cell niche 4,[8][9][10] .Germ cell proliferation can be rescued in inx-8(0) inx-9(0) mutants to half the level of wild type by driving inx-8 expression in the DTC with the lag-2 promoter 3 . In these animals, gap junctions between soma and germline are established in the distal gonad arm, but ostensibly not in the proximal arm; many resultant embryos exhibit characteristics of the Pod phenotype (Polarity and Osmotic sensitivity Defect)...

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Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

Cited by 179 publications

References 58 publications

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

Short-chain fatty acid, acylation and cardiovascular diseases

Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis inCaenorhabditis elegans

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