Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis

Diebold, Lauren; Gil, Hyea Jin; Gao, Peng; Martínez, Carlos A.; Weinberg, Samuel E.; Chandel, Navdeep S.

doi:10.1038/s42255-018-0011-x

Cited by 154 publications

(148 citation statements)

References 57 publications

(74 reference statements)

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“…We observed decreased glycolytic intermediates in HMEC-1 cells after long-term hypoxia, while other studies in distinct types of endothelial cells in hypoxia or of tumor endothelial cells in vivo observed increased glycolysis (34,64–66). However, our data are consistent with decreased glycolytic metabolites observed in a mouse model with endothelial cell-specific ETC deficiency (63). These results highlight the need for development of models that most accurately represents tumor endothelial cells exposed to hypoxia in order to identify robust metabolic differences.…”

Section: Discussionsupporting

confidence: 91%

“…However, we found that neither aspartate nor electron acceptors were able to rescue the growth defect of HMEC-1 cells in hypoxia, indicating that these are not the primary mechanism for reduced cell proliferation (S4 Fig B and D-G). There is precedent that the primary functional uses of aspartate differ in endothelial cells compared to cancer cells: ETC inhibition in HUVEC endothelial cells led to a decrease in aspartate and lower cell proliferation, but addition of aspartate did not rescue proliferation (63). Despite differences in the endothelial cell types and perturbations, the concordance of these findings indicates that aspartate has unique roles in endothelial cells experiencing oxidative stress, which differ from the mechanisms observed in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

Cohen

Geck

Toker

2020

Preprint

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21 The vasculature within a tumor is highly disordered both structurally and functionally. Endothelial 22 cells that comprise the vasculature are poorly connected causing vessels to be leaky and exposing 23 the endothelium to a hypoxic microenvironment. Therefore, most anti-angiogenic therapies are 24 generally inefficient and result in acquired resistance to increased hypoxia due to elimination of 25 the vasculature. Recent studies have explored the efficacy of targeting metabolic pathways in 26 tumor cells in combination with anti-angiogenic therapy. However, the metabolic alterations of 27 endothelial cells in response to hypoxia has been relatively unexplored. Here, we measured polar 28 metabolite levels in microvascular endothelial cells exposed to short-and long-term hypoxia with 29 the goal of identifying metabolic vulnerabilities that can be targeted to normalize tumor 30 vasculature and improve drug delivery. Many amino acid-related metabolites were altered by 31 hypoxia exposure, especially within alanine-aspartate-glutamate, serine-threonine, and cysteine-32 methionine metabolism. Additionally, there were significant changes in de novo pyrimidine 33 synthesis as well as glutathione and taurine metabolism. These results provide key insights into 34 the metabolic alterations that occur in endothelial cells in response to hypoxia, which serve as a 35 foundation for future studies to develop therapies that lead to vessel normalization and more 36 efficient drug delivery. Introduction 38The tumor vasculature is highly disordered with both dense regions of vessels and areas 39 that lack vessels. This leads to inefficient blood flow and delivery of nutrients to a tumor, resulting 40 in a microenvironment that is nutrient-poor and hypoxic (1-3). The endothelial cells that comprise 41 disordered vessels are not tightly connected, resulting in leaky vessels (4,5) and exposing 3 42 endothelial cells to a hypoxic environment. This leakiness also enables tumor cell intravasation 43 and metastasis, and significantly impedes efficient drug delivery to tumors (1,3,6-9). Therefore, a 44 number of therapeutic approaches in cancer treatment have focused on normalizing the disordered 45 tumor vasculature. 46Traditionally, the goal of anti-angiogenic therapies (AATs) was to eradicate the vasculature 47 and deprive tumors of nutrients (10). Many AATs are approved or in clinical trials for treatment 48 of solid tumors as monotherapies or in combination with chemotherapy (9,11-15). However, 49 tumors adapt to the hypoxic microenvironment induced by AATs and develop resistance to therapy 50 (16-22). To overcome these limitations, an alternative approach to targeting the tumor vasculature 51 has been explored, whereby pruning and normalization of the tumor vasculature promotes the 52 highly ordered vasculature found within normal tissues. The resulting increased oxygenation and 53 blood flow in turn allows efficient drug delivery (1,3,23). Normalization of the tumor vasculature 54 has been achieved in several clinical studies f...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

Cohen

Geck

Toker

2020

Preprint

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“…The proliferation and migration of endothelial cells are essential for neo-vessel formation [1,2]. As expected, the proliferation and migration of endothelial cells during angiogenesis require an adequate supply of energy [3][4][5]. In addition to being the powerhouse of the cell, mitochondria also play critical roles in reactive oxygen species (ROS) generation, Ca 2+ homeostasis, and cell death [6][7][8].…”

Section: Introductionmentioning

confidence: 94%

Mitochondrial MiRNA in Cardiovascular Function and Disease

Song

Zhang

2019

Cells

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MicroRNAs (miRNAs) are small noncoding RNAs functioning as crucial post-transcriptional regulators of gene expression involved in cardiovascular development and health. Recently, mitochondrial miRNAs (mitomiRs) have been shown to modulate the translational activity of the mitochondrial genome and regulating mitochondrial protein expression and function. Although mitochondria have been verified to be essential for the development and as a therapeutic target for cardiovascular diseases, we are just beginning to understand the roles of mitomiRs in the regulation of crucial biological processes, including energy metabolism, oxidative stress, inflammation, and apoptosis. In this review, we summarize recent findings regarding how mitomiRs impact on mitochondrial gene expression and mitochondrial function, which may help us better understand the contribution of mitomiRs to both the regulation of cardiovascular function under physiological conditions and the pathogenesis of cardiovascular diseases.

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“…Histones were pelleted at 10,000 g for 5 min, washed once with 0.1% HCl in acetone, twice with 100% acetone followed by centrifugation at 15,000 g for 5 min, and then briefly air-dried. Histones were derivatized, digested and analyzed by targeted LC-MS/MS as described previously 67–69 .…”

Section: Methodsmentioning

confidence: 99%

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

Kusi

Zand

Lin

et al. 2020

Preprint

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17Metabolic reprogramming in cancer cells not only sustains bioenergetic and biosynthetic needs 18 but also influences transcriptional programs, yet how chromatin regulatory networks are rewired 19 by altered metabolism remains elusive. Here we investigate genome-scale chromatin remodeling 20 in response to 2-hydroxyglutarate (2HG) oncometabolite using single-cell assay for transposase 21 accessible chromatin with sequencing (scATAC-seq). We find that 2HG enantiomers differentially 22 disrupt exquisite control of epigenome integrity by limiting α-ketoglutarate (αKG)-dependent DNA 23 and histone demethylation, while enhanced cell-to-cell variability in the chromatin regulatory 24 landscape is most evident upon exposure to L2HG enantiomer. Despite the highly heterogeneous 25 responses, 2HG largely recapitulates two prominent hallmarks of the breast cancer epigenome, 26 i.e., global loss of 5-hydroxymethylcytosine (5hmC) and promoter hypermethylation, particularly 27 at tumor suppressor genes involved in DNA damage repair and checkpoint control. Single-cell 28 mass cytometry further demonstrates downregulation of BRCA1, MSH2 and MLH1 in 2HG-29 responsive subpopulations, along with acute reversal of chromatin remodeling upon withdrawal. 30 Collectively, this study provides a molecular basis for metabolism-epigenome coupling and 31 identifies metabolic vulnerabilities imposed on the breast cancer epigenome. 33 As a dynamic system, cancer cells continuously adapt to the fluctuating microenvironment by 34 rerouting metabolic fluxes and evolve from early initiation through progression and 35 dissemination 1,2 . Metabolic reprogramming in cancer cells facilitates energy production and 36 macromolecular synthesis to fuel cell proliferation 3,4 . In addition to supporting bioenergetic and 37 biosynthetic needs, altered metabolism involves promiscuous production of non-canonical 38 metabolic intermediates, which have been described as metabolic waste products or metabolite 39 damage 5,6 . Recent studies suggest that these previously uncharacterized metabolites including 40 oncometabolites are linked to 'non-metabolic' signaling mechanisms in cell-type-specific fate 41 decisions 7 . 42 The oncometabolite 2-hydroxyglutarate (2HG) occurs as two enantiomers and 43 accumulates up to millimolar concentrations in a broad range of hematological and solid 44 malignancies 8,9 . Somatic mutations in isocitrate dehydrogenase genes, IDH1 and IDH2, found in 45 glioma and acute myeloid leukemia (AML) result in stereospecific production of the D-enantiomer 46 (D2HG) 10,11 , while breast tumors frequently exhibit elevated levels of 2HG despite the lack of IDH 47 mutations 12,13 . Recent studies indicate that the L-enantiomer (L2HG) can accumulate under 48 acidic 14,15 and hypoxic conditions 16,17 that often coexist in the tumor microenvironment, yet the 49 potential sources and functions of L2HG are less well established. Both enantiomers structurally 50 resemble α-ketoglutarate (αKG), a key intermediate ...

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Mitochondrial complex III is necessary for endothelial cell proliferation during angiogenesis

Cited by 154 publications

References 57 publications

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia

Mitochondrial MiRNA in Cardiovascular Function and Disease

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

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