Abstract: SA-PO144
Transcription Factor BACH1 in Promoting Mitochondrial Dysfunction of Kidney Ischemia-Reperfusion Injury via Mitochondrial Glutathione Depletion
Session Information
- AKI: Metabolism and Cell Death
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Jun, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- Li, Xiaolin, Jiangnan University Wuxi School of Medicine, Wuxi, Jiangsu, China
- Zhang, Hui, Jiangnan University Wuxi School of Medicine, Wuxi, Jiangsu, China
- Lu, Jingyao, Jiangnan University Wuxi School of Medicine, Wuxi, Jiangsu, China
Background
The hypothesis is that BACH1 induce mitochondrial glutathione(mtGSH) depletion through inhibiting SLC25A39 expression. The study aims to clarify the novel molecular pathogenesis of BACH1 on the renal ischemia-reperfusion induced-mitochondrial dysfunction, and provide a new intervention target for acute renal ischemia-reperfusion injury.
Methods
In vivo renal ischemia-reperfusion injury model(I/R) was established using C57BL/6J wild-type mice and BACH1 gene-knockout mice (BACH1-/-) respectively. Invitro anoxia-reoxygenation injury model(H/R) was established using human proximal tubular cells (HK-2) strain. BACH1 gene was silenced or overexpressed respectively, and SLC25A39 gene was also silenced. The effect of BACH1 on the transcriptional activity of SLC25A39 was detected by the luciferase reporter gene and Electrophoretic mobility shift assay (EMSA). The oxidative stress and mitochondrial function indexes were also measured.
Results
The renal expression of BACH1 increased, yet the renal expressions of SLC25A39 and mtGSH contents decreased significantly in patients with acute ischemic tubular injury and renal ischemia-reperfusion injury mice models. BACH1 deletion up-regulated renal expression of SLC25A39 and mtGSH contents, yet decreased mitochondrial oxidative stress index, leading to improved mitochondrial function in BACH1-/- mice following renal ischemia-reperfusion injury.
In HK-2 cells subject to anoxia-reoxygenation injury, BACH1 gene overexpression down-regulated the expression of SLC25A39 and mtGSH contents, increased mitochondrial oxidative stress, leading to mitochondrial dysfunction. And BACH1siRNA up-regulated the expression of SLC25A39 and mtGSH contents, yet decreased mitochondrial oxidative stress, leading to improved mitochondrial function. Intriguingly, BACH1siRNA increased mtGSH contents and improved mitochondrial function in anoxia-reoxygenation HK-2 cells pretreated with GSH ethyl-ester.
Luciferase reporter gene detection and EMSA confirmed the binding site between BACH1 and SLC25A39 promoter region.
Conclusion
BACH1 induced mitochondrial glutathione depletion through inhibition of SLC25A39 expression, leading to mitochondrial dysfunction of renal ischemia-reperfusion injury.
Funding
- Government Support – Non-U.S.