# Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation

## TL;DR

Low-dose radiation causes lasting stress in blood stem cells, leading to mitochondrial issues and reduced long-term stem cell function.

## Contribution

Discovery that heritable ER stress from low-dose irradiation causes mitochondrial and epigenetic defects in hematopoietic stem cells.

## Key findings

- Low-dose irradiation causes ER stress leading to mitochondrial dysfunction in hematopoietic stem cells.
- Heritable ER stress results in long-term stem cell exhaustion and DNA hypomethylation.
- Inhibiting ER stress early can partially reverse DNA hypomethylation in irradiated stem cells.

## Abstract

How hematopoietic stem cells (HSCs) respond to low doses of radiation currently used in medicine is largely unknown. Here, we show that HSC exposed to a single 20 mGy dose of irradiation (20 mGy-HSC) exhibit, when proliferating, oxidative stress and altered metabolism associated with increased mitochondrial reactive oxygen species and mitochondrial Ca2+ overload. These mitochondrial defects arise from immediate and sustained endoplasmic reticulum (ER) stress, induced by proliferative 20 mGy-HSC through the activation of the eIF2α-ATF4 branch of the unfolded protein response (UPR). The ER stress is heritable and leads, in long-term quiescent 20 mGy-HSC, to the activation of the IRE1α-Xbp1 branch of UPR, which fails to restore ER homeostasis, resulting in a decreased long-term HSC pool. Finally, we show that this heritable ER stress leads to global DNA hypomethylation, partially reversed by the early inhibition of ER stress. Our studies illuminate how adaptive ER stress responses can lead to mitochondrial defects and HSC dysfunctions.

•Irradiated HSC at 20 mGy shows mitochondrial dysfunctions due to heritable ER stress•Depending on the 20 mGy-HSC physiological state, different branches of UPR are activated•The heritable ER stress of 20 mGy-HSC results in long-term HSC exhaustion•ER stress leads to HSC DNA hypomethylation, partially reversed by its inhibition

Irradiated HSC at 20 mGy shows mitochondrial dysfunctions due to heritable ER stress

Depending on the 20 mGy-HSC physiological state, different branches of UPR are activated

The heritable ER stress of 20 mGy-HSC results in long-term HSC exhaustion

ER stress leads to HSC DNA hypomethylation, partially reversed by its inhibition

Cell biology