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Publication

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

Cell metabolism | 2018

The role of phosphoglycerate dehydrogenase (PHGDH), a key enzyme of the serine synthesis pathway (SSP), in endothelial cells (ECs) remains poorly characterized. We report that mouse neonates with EC-specific PHGDH deficiency suffer lethal vascular defects within days of gene inactivation, due to reduced EC proliferation and survival. In addition to nucleotide synthesis impairment, PHGDH knockdown (PHGDHKD) caused oxidative stress, due not only to decreased glutathione and NADPH synthesis but also to mitochondrial dysfunction. Electron transport chain (ETC) enzyme activities were compromised upon PHGDHKD because of insufficient heme production due to cellular serine depletion, not observed in other cell types. As a result of heme depletion, elevated reactive oxygen species levels caused EC demise. Supplementation of hemin in PHGDHKD ECs restored ETC function and rescued the apoptosis and angiogenesis defects. These data argue that ECs die upon PHGDH inhibition, even without external serine deprivation, illustrating an unusual importance of serine synthesis for ECs.

Pubmed ID: 30017355 RIS Download

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Associated grants

Agency: NIGMS NIH HHS, United States
Id: T32 GM007287
Agency: NCI NIH HHS, United States
Id: R01 CA201276
Agency: NCI NIH HHS, United States
Id: R21 CA198028
Agency: Howard Hughes Medical Institute, United States

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