Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells

Abstract

Oxidative stress-induced cell damage is involved in many neurological diseases. Interferon regulatory factor 6 (IRF6), a member of the IRF family of transcription factors, is required for the differentiation of skin, breast epithelium, and oral epithelium. However, the regulation and function of IRF6 in central nervous system remain unknown. This study aimed to investigate the role of IRF6 in hydrogen peroxide (H2O2)-induced oxidative neuronal injury in HT22 mouse hippocampal cells. Treatment with H2O2 significantly increased the expression of IRF6 at both mRNA and protein levels, and knockdown of IRF6 using specific small interfering RNA reduced H2O2-induced cytotoxicity, as evidenced by increased cell viability and decreased apoptosis. Knockdown of IRF6 attenuated intracellular reactive oxygen species (ROS) generation and lipid peroxidation, and also preserved endogenous antioxidant enzyme activities. The inhibitory effect of IRF6 knockdown on mitochondrial dysfunction was demonstrated by reduced mitochondrial oxidative level, preserved mitochondrial membrane potential (MMP) and ATP generation, as well as attenuated mitochondrial swelling. In addition, down-regulation of IRF6 inhibited the activation of mitochondrial apoptotic factors, whereas IRF6 knockdown together with caspase inhibitors had no extra effect on cell viability and LDH release. These results suggest that knockdown of IRF6 has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on preservation of mitochondrial function.

Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway

“…At the same time, mitochondrial dysfunction promotes abnormalities in the mitochondrial respiratory chain’s electron transport pathways, ultimately interfering with the intracellular ATP production [5,32]. Consistent with previous studies [33,34,35], current studies have shown that when cells are exposed to H 2 O 2 , the MMP levels and ATP content are significantly reduced compared to controls, whereas the co-treatment with glutathione significantly reverses the H 2 O 2 -induced loss of MMP and APT. However, in the presence of ZnPP, the glutathione-mediated repair of the mitochondrial dysfunction and decreased production of ATP were significantly diminished.…”

Protective Effect of Phloroglucinol on Oxidative Stress-Induced DNA Damage and Apoptosis through Activation of the Nrf2/HO-1 Signaling Pathway in HaCaT Human Keratinocytes

“…However, HO-1 activation is recognized as a cell protection mechanism against oxidative stress-mediated mitochondrial dysfunction through inactivation of the mitochondria-mediated intrinsic apoptosis pathway [26,27]. Consistent with previous studies [38,39,40], the present study shows that when cells were exposed to H 2 O 2 , MMP levels and ATP contents were significantly reduced compared to controls, whereas PG significantly reversed the H 2 O 2 -induced loss of MMP and APT. However, in the presence of ZnPP, PG-mediated repair of mitochondrial dysfunction and the decreased production of ATP were significantly abolished.…”

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

“…ZBTB20 is also highly expressed uniquely in SEGAs, and is a transcriptional repressor with roles in neurogenesis, glucose homeostasis, and postnatal growth [48]. IRF6 (Interferon regulatory factor 6) plays a role in regulating mammary epithelial cell proliferation, while specifically expressed in SEGAs in comparison to other brain tumors but is expressed in other cancers and normal tissues [49]. These top genes have been reported to be epigenetically regulated bearing histone modifications: H3K27 trimethylation (H3K27me3) mark in brain for HMX2, HMX3, IRF6; H3K4me2 and H3K27me3 in neural precursor cells (NPC) for HMX2, HMX3, and VAX1 [50].…”