title: CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease.
abstract: Mitochondrial dysfunction, often characterized by massive fission and other morphological abnormalities, is a well-known risk factor for Alzheimer's disease (AD). One causative mechanism underlying AD-associated mitochondrial dysfunction is thought to be amyloid-β (Aβ), yet the pathways between Aβ and mitochondrial dysfunction remain elusive. In this study, we report that CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Aβ-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed Aβ undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with Aβ. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in Aβ-treated cells. Conversely, Crif1 overexpression prevented Aβ-induced mitochondrial dysfunction and cell death. Finally, we show that Aβ-induced downregulation of Crif1 is mediated by enhanced reactive oxygen species (ROS) and ROS-dependent sumoylation of the transcription factor specificity protein 1 (Sp1). These results identify the ROS-Sp1-Crif1 pathway to be a new mechanism underlying Aβ-induced mitochondrial dysfunction and suggest that ROS-mediated downregulation of Crif1 is a crucial event in AD pathology. We propose that Crif1 may serve as a novel therapeutic target in the treatment of AD.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: S M
authors.initials: SM
authors.lastname: Son
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Cha
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Shong
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Hwang
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: 1] Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul, Korea [2] Department of Neurology and Pathology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
authors.forename: K-S
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; C527307:Crif1 protein, mouse; C476586:GADD45GIP1 protein, human; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor