title: Overexpression of MTERF4 promotes the amyloidogenic processing of APP by inhibiting ADAM10.
abstract: Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ) peptide in the brain, which is produced by the proteolysis of β-amyloid precursor protein (APP). Recently, the mitochondrial transcription factor 4 (MTERF4), a member of the MTERF family, was implicated in regulating mitochondrial DNA transcription and directly in controlling mitochondrial ribosomal translation. The present study identified a novel role for MTERF4 in shifting APP processing toward the amyloidogenic pathway. The levels of MTERF4 protein were significantly increased in the hippocampus of APP/PS1 mice. In addition, the overexpression of MTERF4 induced a significant increase in the levels of APP protein and secreted Aβ42 in HEK293-APPswe cells compared with control cells. Further, MTERF4 overexpression shifted APP processing from α-to β-cleavage, as indicated by decreased C83 levels and elevated C99 levels. Finally, the MTERF4 overexpression suppressed a disintegrin and metalloproteinase 10 (ADAM10) expression via a transcriptional mechanism. Taken together, these results suggest that MTERF4 promotes the amyloidogenic processing of APP by inhibiting ADAM10 in HEK293-APPswe cells; therefore, MTERF4 may play an important role in the pathogenesis of AD.
authors.affiliation: Department of Clinical Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Clinical Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: qingliu5566@aliyun.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Chen
authors.affiliation: Department of Clinical Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Li
authors.affiliation: Department of Clinical Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Ding
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016564:Amyloid beta-Protein Precursor; C560500:MTERF4 protein, human; C000619858:MTERF4 protein, mouse; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D000072197:ADAM10 Protein
keywords: ADAM10; Alzheimer's disease; Amyloid precursor protein; BACE1; MTERF4