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NOTCH1 and Endothelial Mitochondrial Metabolism

ABSTRACT: Notch signaling activation drives endothelial-to-mesenchymal transition (EndMT), which is key to heart development. Accumulating evidence indicates that endothelial cell metabolism reprogramming regulates endothelial function independent of canonical cell signaling. Herein, we investigated whether and how Notch signaling and metabolism reprogramming crosstalk in the EndMT process. We found Notch1 intracellular domain (NICD1) was localized within the mitochondria of endothelial cells and interacted with the PDH E1 subunit beta, influencing the phosphorylation of the PDH E1 subunit alpha, thereby activating PDH and enhancing mitochondrial metabolism.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jie Wang

LAB HEAD: Jian-Yuan Zhao

PROVIDER: PXD054146 | Pride | 2025-01-18

REPOSITORIES: pride

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			Action	DRS
	WJ-NICD.msf	Msf
	WJ-NICD.raw	Raw
	WJ-NICD.xlsx	Xlsx
	WJ-PCDNA.msf	Msf
	WJ-PCDNA.raw	Raw

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Publications

NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.

Wang Jie J Zhao Rui R Xu Sha S Zhou Xiang-Yu XY Cai Ke K Chen Yu-Ling YL Zhou Ze-Yu ZY Sun Xin X Shi Yan Y Wang Feng F Gui Yong-Hao YH Tao Hui H Zhao Jian-Yuan JY

Nature communications 20241116 1

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where ...[more]

PMID: 39550366

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Endothelial Cells from different anatomical origin have distinct responses during Snail/TGF-β2-mediated Endothelial-Mesenchymal Transition

Project description:Endothelial-mesenchymal transition (EndMT) is a complex process, in which differentiated endothelial cells undergo phenotypic transition to mesenchymal cells. Given the diversity of the vascular system in architecture, structure, and embryonic origins, it is not clear if endothelial cells lining different vessels are able to undergo EndMT. Therefore, the aim of this study was to evaluate the molecular and functional changes that occur in different types of endothelial cells after induction of EndMT through overexpression of Snail and TGF-β2. Different types of endothelial cells (human umbilical vein, heart, and lung) have distinct response when induced to undergo EndMT. Coronary artery endothelial cells (HCAEC) induced with combined Snail overexpression plus TGF-β2 treatment promotes a decrease of endothelial markers, an increase of mesenchymal markers and migration. The mechanism that HCAEC undergoing EndMT may be mediated through Notch and non-canonical Wnt signaling pathways. These results provide the foundation for understanding the roles of specific signaling pathways in mediating EndMT in endothelial cells from different anatomical origin.

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Unusual composition of the mitochondrial pyruvate dehydrogenase complex from the widespread marine protist group diplonemids

Project description:In eukaryotes, pyruvate, a key metabolite produced by glycolysis, is converted by a mitochondrial pyruvate dehydrogenase complex (PDH) to acetyl-coenzyme A, which is fed into the tricarboxylic acid cycle. Two additional enzyme complexes catalyze similar oxidative decarboxylation reactions albeit using different substrates, the branched-chain ketoacid dehydrogenase (BCKDH) and the 2-oxoglutarate dehydrogenase (OGDH). In diplonemids, one of the most abundant and diverse groups of oceanic protists, comparative transcriptome analyses indicated that their PDH complex is compositionally unique, with the conventional E1 subunit replaced by an aceE protein of prokaryotic origin. Here we demonstrate in the model diplonemid Paradiplonema papillatum that the pyruvate dehydrogenase activity is comparable to that in other euglenozoan protists. By protein mass spectrometry we revealed that the aceE protein is twice as abundant as the E1 subunits of OGDH and enriched in the mitochondrion to the same level as the BCKDH E1 subunits, corroborating the functional relevance of the proposed aceE subunit of the PDH complex. Importantly, the acquisition of the archaeal aceE by the diplonemid ancestor led not only to the complete loss of the eukaryotic-type E1 of the PDH complex, but also its dedicated E2 and E3 subunits, still present in other euglenozoans. Hence, to reconstitute the diplonemid PDH, the aceE protein needs to partner with E2 and E3 subunits of BCKDH and/or OGDH. The diplonemid example illustrates that the acquisition and successful integration of a foreign E1p can profoundly reorganize the entire PDH complex.

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Gene expression of HUVECS treated with either siRNA to CTRL, PDHA1, or SREBF2 and treated with TNF 16 hours

Project description:The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism, however, the function and regulation of elevated mitochondrial metabolism in EC in response to pro-inflammatory cytokines remains unclear. Using high-resolution metabolomics and 13C-glucose labeled flux techniques, we demonstrate that pyruvate dehydrogenase activity (PDH) and tricarboxylic acid cycle flux is elevated in human umbilical vein ECs (HUVECs) in response to overnight (16 hrs) treatment with TNFα (10 ng/mL). Mechanistic studies indicate that TNFα mediates these metabolic changes via mitochondrial specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB dependent mechanism. Using RNA sequencing following siRNA mediated knockdown of the catalytically active subunit of PDH, PDHE1a (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are upregulated by TNFa stimulation. Notably, TNFa induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Using metabolomics and ChIP sequencing (H3AcK27), we demonstrate that TNFα induced PDH flux promotes histone acetylation of specific gene sets via citrate accumulation and ATP-citrate lyase activity. Together, these results indicate that targeting endothelial glucose oxidation and/or acetyl CoA generation may offer a novel therapeutic strategy in the treatment of vascular inflammation.

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Gene expression of HUVECS treated with either siRNA to CTRL or PDHA1 and treated with TNF 16 hours

Project description:The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimulileads to an increase in mitochondrial metabolism, however, the function and regulation of elevated mitochondrial metabolism in EC in response to pro-inflammatory cytokines remains unclear. Using high-resolution metabolomics and13C-glucose labeled flux techniques, we demonstrate thatpyruvate dehydrogenase activity (PDH) and tricarboxylic acid cycle flux is elevated in human umbilical vein ECs (HUVECs) in response to overnight (16 hrs) treatment withTNFα (10 ng/mL).Mechanistic studies indicate thatTNFα mediates these metabolic changes via mitochondrial specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB dependent mechanism. Using RNA sequencing following siRNA mediated knockdown of thecatalytically active subunit of PDH, PDHE1a(PDHA1 gene), we show that PDH fluxcontrols the transcription of approximately one-third of the genes that are upregulated by TNFastimulation. Notably, TNFainduced PDHflux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules.Using metabolomics and ChIP sequencing (H3AcK27), we demonstrate that TNFα induced PDH flux promotes histone acetylation of specific gene sets via citrate accumulation and ATP-citrate lyase activity.Together, these resultsindicate that targeting endothelial glucose oxidation and/or acetyl CoA generation may offer a novel therapeutic strategy in the treatment of vascular inflammation.

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The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition [microarray]

Project description:Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under pro-inflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT promoting pro-inflammatory and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes and prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting pro-inflammatory and hypoxic conditions and support the acquirement of a mesenchymal phenotype.

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