The UPR reduces glucose metabolism via IRE1 signaling

Abstract

Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response.

Melatonin attenuates mitochondrial and metabolic dysfunction caused by leptin deficiency

“…A shift in energy balance by dietary alterations and increased oxidative stress levels may play an important role in the mechanisms governing protein homeostasis like the UPR (van der Harg et al, 2017, Yilmaz, 2017. In contrast to our findings, several studies have demonstrated increased ER stress and a consequent activation of the UPR in chronic metabolic diseases such as obesity (Hotamisligil, 2010, Ozcan, Cao et al, 2004.…”

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

“…This finding is in line with a recent report demonstrating that silencing XBP1 in glioma cells inhibits glycolysis resulting in reduced ATP production and decreased cancer cell survival [ 26 ]. Long-term activation of the IRE1 signaling has also been shown to reduce glucose metabolism and mitochondrial function; however, it is unclear whether this effect is mediated by XBP1 [ 27 ]. Intriguingly, deficiency of XBP1 has been shown to induce an overactivation of IRE1, contributing to enhanced inflammation and apoptosis [ 28 ].…”

Endoplasmic reticulum stress signalling – from basic mechanisms to clinical applications

“…The ER is a site of significant metabolic regulation. The UPR plays a major role in the regulation of glycolysis and it was recently shown that IRE1 mediates a metabolic decrease upon glucose shortage in neurons, suggesting an important role for the UPR as an adaptive response mechanism in relation to energy metabolism [291]. Moreover, mTOR signalling adjusts global protein synthesis, which is a highly energy consuming process, and thereby regulates energy metabolism (reviewed in [292]).…”