Serine Synthesis via PHGDH Is Essential for Heme Production in Endothelial Cells

Vandekeere, Saar; Dubois, Charlotte; Kalucka, Joanna; Sullivan, Mark R.; García-Caballero, Melissa; Goveia, Jermaine; Chen, Rongyuan; Diehl, Frances F.; Bar-Lev, Libat; Souffreau, Joris; Pircher, Andreas; Kumar, Saran; Vinckier, Stefan; Hirabayashi, Yoshio; Furuya, Shigeki; Schoonjans, Luc; Eelen, Guy; Ghesquière, Bart; Keshet, Eli; Li, Xuri; Heiden, Matthew G. Vander; Dewerchin, Mieke; Carmeliet, Peter

doi:10.1016/j.cmet.2018.06.009

Cited by 152 publications

(158 citation statements)

References 47 publications

(85 reference statements)

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“…Previous studies have shown that PHGDH is highly expressed in radial glial cells, antitumor CD8+ T-cells, astrocytes, macrophages, and endothelial cells. 52,59 Humans with hypomorphic mutations in PHGDH exhibit developmental delay and mental retardation, both of which can be ameliorated by serine supplementation, suggesting that transitory PHGDH inhibition following completion of neuronal development may be tolerable. While our study found no evidence of neurotoxicity and weight loss due to PHGDH inhibition, future studies will be needed to determine whether PHGDH inhibition needs to be staggered with therapies that require functional PHGDH-dependent cells, such as cytotoxic CD8+ T-lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

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Kim

Osorio-Vasquez

et al. 2020

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A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

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Section: Discussionmentioning

confidence: 99%

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

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Kim

Osorio-Vasquez

et al. 2020

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“…Heme and heme-containing enzymes play a significant role in this process, but the linkage between these phenomena has not been extensively explored. Serine synthesis deficiency induced heme depletion in ECs and caused decreased mitochondrial respiration and multiorgan angiogenic defects in animals (Vandekeere et al, 2018), while heme accumulation in ECs due to an altered heme exporter affects angiogenesis and causes endoplasmic reticulum stress (Petrillo et al, 2018). Apart from ECs, nonsmall cell lung carcinoma cells with elevated heme synthesis levels had increases in enzyme activities of the ETC.…”

Section: Discussionmentioning

confidence: 99%

“…Severe heme depletion could possibly disrupt NADH/H + and redox homeostasis, as already evident from ETC dysfunction. Moreover, increased ROS levels in ECs can shift their metabolic needs to accommodate cellular damage and dysfunction, in which case both cellular energetic systems are collapsed (Vandekeere et al, 2018;Warren et al, 2014;Wellen and Thompson, 2010).…”

Section: Discussionmentioning

confidence: 99%

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

Shetty

Sishtla

Park

et al. 2019

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The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe 2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.

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“…Consistently, SFXN1 is a constituent of the 442 mitochondrial heme metabolon (Medlock et al, 2015). In endothelial cells, depletion of cellular 443 serine by deletion of PHGDH, encoding the rate-limiting enzyme in de novo serine biosynthesis, 444 results in inadequate heme and impedes OXPHOS capacity (Vandekeere et al, 2018). In our 445…”

Section: Loss Of Sfxn1 Causes Complex Iii-related Defectsmentioning

confidence: 95%

The mitochondrial carrier SFXN1 is critical for Complex III integrity and cellular metabolism

Acoba

Alpergin

Renuse

et al. 2020

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19 20 Mitochondrial carriers (MC) mediate the passage of small molecules across the inner 21 mitochondrial membrane (IMM) enabling regulated crosstalk between compartmentalized 22 reactions. Despite MCs representing the largest family of solute carriers in mammals, most have 23 not been subjected to a comprehensive investigation, limiting our understanding of their 24 metabolic contributions. Here, we functionally characterized SFXN1, a member of the non-25 canonical, sideroflexin MC family. We find that SFXN1, an integral membrane protein in the IMM 26 with an uneven number of transmembrane domains, is a novel TIM22 substrate. SFXN1 27 deficiency specifically impairs Complex III (CIII) biogenesis, activity, and assembly, 28 compromising coenzyme Q levels. This CIII dysfunction is independent of one-carbon 29 metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, 30 SFXN1 supports CIII function by participating in heme and central carbon metabolism. Our 31 findings highlight the multiple ways that SFXN1-based amino acid transport impacts 32 mitochondrial and cellular metabolic efficiency. 33 34 Keywords: mitochondria, mitochondrial carrier, sideroflexin, SFXN1, Complex III, OXPHOS, 35 amino acid, serine, heme, metabolism 36 explained by a defective 1C metabolism, which represents the only well-documented 99 physiological role for SFXN1 (Kory et al., 2018). Instead, we show that SFXN1 is important for 100 heme and central carbon metabolism, both of which support CIII function to varying extents. 101Collectively, these data define additional roles and thus provide a richer context for how SFXN1-102 mediated amino acid transport maintains mitochondrial integrity and promotes metabolic 103 plasticity. 104 RESULTS 105

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Serine Synthesis via PHGDH Is Essential for Heme Production in Endothelial Cells

Cited by 152 publications

References 47 publications

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

The mitochondrial carrier SFXN1 is critical for Complex III integrity and cellular metabolism

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