title: FAM3A attenuates ER stress-induced mitochondrial dysfunction and apoptosis via CHOP-Wnt pathway.
abstract: Endoplasmic reticulum (ER) stress is linked to several neurological disorders, and neuronal injury cascades initiated by excessive ER stress are mediated, in part, via mitochondrial dysfunction. In the present study, we identified FAM3A as an important regulator of ER stress-induced cell death in neuronal HT22 cells. The ER stress inductor tunicamycin (TM) significantly decreased the expression of FAM3A at both mRNA and protein levels, which was shown to be dependent on the induction of reactive oxygen species (ROS). Overexpression of FAM3A attenuated TM-induced apoptosis and activation of ER stress factors, but had no effect on ER calcium metabolism in HT22 cells. We also found decreased mitochondrial ROS generation, inhibited cytochrome c release and preserved mitochondrial membrane potential (MMP) in FAM3A overexpressed cells. In addition, the experiments using isolated mitochondria showed that overexpression of FAM3A attenuated mitochondrial swelling and loss of mitochondrial Ca(2+) buffering capacity after TM exposure. By using specific targeted small interfering RNA (siRNA) to knockdown the expression of the C/EBP homologous protein (CHOP), we found that FAM3A-induced protection and inhibition of ER stress was mediated by inverting TM-induced decrease of Wnt through the CHOP pathway. Our study demonstrates a pivotal role of FAM3A in protecting against TM-induced cytotoxicity via regulating CHOP-Wnt pathway, and suggests the therapeutic values of FAM3A overexpression against ER stress-associated neuronal injury.
authors.affiliation: Department of Obstetrics and Gynecology, the First Affiliated Hospital, Xian Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China. Electronic address: songqing_xjedu@126.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Obstetrics and Gynecology, the First Affiliated Hospital, Xian Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China.
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Gou
authors.affiliation: Department of Obstetrics and Gynecology, the First Affiliated Hospital, Xian Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D014415:Tunicamycin / Q000633:toxicity; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; C497250:Ddit3 protein, mouse; C000588926:FAM3A protein, mouse; D014415:Tunicamycin; D051742:Transcription Factor CHOP
keywords: CHOP; ER stress; FAM3A; Mitochondrial dysfunction; Wnt