Byun, J. Son, Sm Cha, M-Y Shong, M. Hwang, Y. J. Kim, Y. Ryu, H. Moon, M. Kim, K-S Mook-Jung, I. 2024-01-20T07:01:47Z 2024-01-20T07:01:47Z 2021-09-05 2015-06 1350-9047 https://pubs.kist.re.kr/handle/201004/125392 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-beta (A beta), yet the pathways between A beta 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 A beta-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed A beta undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with A beta. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in A beta-treated cells. Conversely, Crif1 overexpression prevented A beta-induced mitochondrial dysfunction and cell death. Finally, we show that A beta-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 A beta-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. English NATURE PUBLISHING GROUP OXIDATIVE STRESS ATP SYNTHASE NEURODEGENERATIVE DISEASES CELL-PROLIFERATION CRISTAE MORPHOLOGY CORTICAL-NEURONS PLAQUE-FORMATION TRANSGENIC MICE ANIMAL-MODEL IN-VIVO CR6-interacting factor 1 is a key regulator in A beta-induced mitochondrial disruption and pathogenesis of Alzheimer's disease Article 10.1038/cdd.2014.184 1 CELL DEATH AND DIFFERENTIATION, v.22, no.6, pp.959 - 973 CELL DEATH AND DIFFERENTIATION 22 6 959 973 scie scopus 000353916700009 2-s2.0-84939985504 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article OXIDATIVE STRESS ATP SYNTHASE NEURODEGENERATIVE DISEASES CELL-PROLIFERATION CRISTAE MORPHOLOGY CORTICAL-NEURONS PLAQUE-FORMATION TRANSGENIC MICE ANIMAL-MODEL IN-VIVO