| First Author | Smith BS | Year | 2023 |
| Journal | Mitochondrion | Volume | 69 |
| Pages | 10-17 | PubMed ID | 36627030 |
| Mgi Jnum | J:344828 | Mgi Id | MGI:7579506 |
| Doi | 10.1016/j.mito.2023.01.001 | Citation | Smith BS, et al. (2023) ER stress-associated transcription factor CREB3 is essential for normal Ca(2+), ATP, and ROS homeostasis. Mitochondrion 69:10-17 |
| abstractText | In mammalian cells, mitochondrial respiration produces reactive oxygen species (ROS) such as superoxide (O(2)(-)), which is then converted by the SOD1 enzyme into hydrogen peroxide (H(2)O(2)), 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 Ca(2+). Mitochondrial Ca(2+) influx from the ER increases ATP and ROS production, while ATP and ROS can regulate Ca(2+) homeostasis, leading to an intricate interplay between Ca(2+), ROS, and ATP synthesis. The Unfolded Protein Response (UPR) proteins ATF6alpha 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 Ca(2+), ROS, and ATP homeostasis. Creb3-deficient mouse embryonic fibroblast cells (MEF(-/-)) were susceptible to H(2)O(2)-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 Ca(2+) release and mitochondrial Ca(2+) levels hinting at a potential cause for MEF(-/-) cell mitochondrial dysfunction. These results suggest that CREB3 is essential for maintaining proper Ca(2+), ATP, and ROS homeostasis in mammalian cells. |
