Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Abstract

Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1a, which is induced specifically by lowdose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to lowdose radiation has important implications in understanding and assessing the health risks of radiation exposure.

MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer

“…A potential molecular mechanism that could facilitate the MUC1-induced metabolic reprogramming could be through HIF-1α. Low dose irradiation enhances HIF-mediated metabolic responses as reported in a recent study (49) and our previous study showed that MUC1-mediated HIF-1α stabilization leads to upregulation of glycolytic and PPP metabolic pathway genes in MUC1-expressing pancreatic cancer cells (18). Our results establish that metabolic responses elicited in MUC1-expressing cells can be effectively targeted using BrPA, which reduces radiation-resistance in pancreatic cancer cells.…”

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

“…For cells and animals, low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis, leading to increased resistance to radiation [42]. In normal cells, a low-oxygen environment generally induces glycolysis [6].…”

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

“…Although mitochondrial remodeling has been observed and proven protective across a number of different stressors (13–15), its potential role in modulating the adaptive response had previously been uncharacterized. Interestingly, Lall et al (61) described an HIF1-dependent metabolic adaptation at 5% O 2 to the adaptive response that involves the induction of a glycolytic program at later time points (12 h). We believe that this adaptation may be attributed to changes in the radiation oxygen effect, in which greater cell death is observed at higher O 2 tension, as previously described by Richardson and Harper (3).…”

“…Our system differs from that of Lall et al . (61) in that experiments were performed at 21% O 2 and the IR adaptation was observed at short time points postirradiation. Taken together, it could be speculated that 2 metabolic processes may regulate the adaptive response at different time points: first, in the short term, mitochondrial remodeling increases metabolic efficiency and ATP production, and secondly, in the longer term, processes induce a metabolic shift toward glycolysis (62, 63), which may limit the damaging ROS production from mitochondria.…”