Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells

Oliver A Stone,Jason K H Lai,Elisabetta Grillo,I-Ching Lee,Stefan Günther,Didier Y R Stainier,Kerstin Wilhelm,Sylvia Jeratsch,Massimo M Santoro,Thomas Braun,Xiaojing Liu,Mohamed El-Brolosy,Carsten Kuenne,Michael Potente,Ana M Romão,Jason W Locasale

doi:10.1038/s41467-018-06406-8

Abstract

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. Here we show that the glycolytic enzyme pyruvate kinase M2 (PKM2) limits glucose oxidation, and maintains the growth and epigenetic state of ECs. We find that loss of PKM2 alters mitochondrial substrate utilization and impairs EC proliferation and migration in vivo. Mechanistically, we show that the NF-κB transcription factor RELB is responsive to PKM2 loss, limiting EC growth through the regulation of P53. Furthermore, S-adenosylmethionine synthesis is impaired in the absence of PKM2, resulting in DNA hypomethylation, de-repression of endogenous retroviral elements (ERVs) and activation of antiviral innate immune signalling. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs.

Highlights

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood
The reduction in labelled lactate was coupled to an increase in [U-13C6]-glucose labelling of citrate (Fig. 1e) and oxygen consumption rate (OCR) (Fig. 1f) in PKM2KD ECs but not in PKMKD ECs, indicating that PKM isoform expression is a critical determinant of the fate of glucose-derived carbon in ECs
These data indicate that branched chain amino acid (BCAA) oxidation, pyruvate anaplerosis and fatty acid oxidation (FAO) are impaired in PKM2KD ECs

Summary

Introduction

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs. The vertebrate vascular system comprises a vast and evolutionarily conserved network that supports tissue growth and homoeostasis[1]. The ability to generate ATP in this manner permits EC migration into non-perfused tissues and allows the expansion of vascular networks during organ growth[2,4,5] Given these distinct metabolic traits, endothelial mitochondria have been considered to function largely as signalling organelles[6,7], and the consequences of enhanced glucose oxidation in ECs are not well described. We show that loss of PKM2 in ECs results in TCA cycle dysfunction, cell cycle arrest and the induction of viral mimicry by endogenous retroviral transcripts

Methods

Results

Conclusion