ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis.

Brandon S Smith, Tristen Hewitt, Marica Bakovic, Ray Lu

Mitochondrion 2023 Mar

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In mammalian cells, mitochondrial respiration produces reactive oxygen species (ROS) such as superoxide (O2-), which is then converted by the SOD1 enzyme into hydrogen peroxide (H2O2), the predominant form of cytosolic ROS. ROS at high levels can be toxic, but below this threshold are important for physiological processes acting as a second messenger similar to Ca2+. Mitochondrial Ca2+ influx from the ER increases ATP and ROS production, while ATP and ROS can regulate Ca2+ homeostasis, leading to an intricate interplay between Ca2+, ROS, and ATP synthesis. The Unfolded Protein Response (UPR) proteins ATF6α and XBP1 contribute to protection from oxidative stress through upregulation of Sod1 and Catalase genes. Here, UPR-associated protein CREB3 is shown to play a role in balancing Ca2+, ROS, and ATP homeostasis. Creb3-deficient mouse embryonic fibroblast cells (MEF-/-) were susceptible to H2O2-induced oxidative stress while having a functioning antioxidant gene expression response compared to MEF+/+. MEF-/- cells also contained elevated basal cytosolic ROS levels, which was attributed to drastically increased basal mitochondrial respiration and spare respiratory capacity relative to MEF+/+. MEF-/- cells also showed an increase in endoplasmic reticulum Ca2+ release and mitochondrial Ca2+ levels hinting at a potential cause for MEF-/- cell mitochondrial dysfunction. These results suggest that CREB3 is essential for maintaining proper Ca2+, ATP, and ROS homeostasis in mammalian cells. Copyright © 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

Citation

Brandon S Smith, Tristen Hewitt, Marica Bakovic, Ray Lu. ER stress-associated transcription factor CREB3 is essential for normal Ca2+, ATP, and ROS homeostasis. Mitochondrion. 2023 Mar;69:10-17