title: HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function.
abstract: The γ-secretase complex (which contains presenilins, nicastrin, anterior pharynx defective-1, and presenilin enhancer-2) cleaves type I transmembrane proteins, including Notch and amyloid precursor protein. Dysregulated γ-secretase activity has been implicated in the pathogenesis of Alzheimer's disease, stroke, atherosclerosis, and cancer. Tight regulation of γ-secretase activity is required for normal physiology. Here, we isolated HIG1 (hypoxia inducible gene 1, domain member 1A) from a functional screen of γ-secretase inhibitory genes. HIG1 was highly expressed in the brain. Interestingly, HIG1 was localized to the mitochondria and was directly bound to γ-secretase components on the mitochondrial membrane in SK-N-SH neuroblastoma cells. Overexpresssion of HIG1 attenuated hypoxia-induced γ-secretase activation on the mitochondrial membrane and the accumulation of intracellular amyloid β. This accumulation was accompanied by hypoxia-induced mitochondrial dysfunction. The latter half domain of HIG1 was required for binding to the γ-secretase complex and suppression of γ-secretase activity. Moreover, depletion of HIG1 increased γ-secretase activation and enhanced hypoxia-induced mitochondrial dysfunction. In summary, HIG1 is a novel modulator of the mitochondrial γ-secretase complex, and may play a role in the maintenance of normal mitochondrial function.
authors.affiliation: Division of Gene Therapy Science, United Graduate School of Child Development, Osaka University, Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Makiko
authors.initials: M
authors.lastname: Takeichi
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Oiki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koriyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Rodriguez
authors.initials: R
authors.lastname: Gerardo Araujo
authors.forename: Akito
authors.initials: A
authors.lastname: Maeda
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Katsuto
authors.initials: K
authors.lastname: Tamai
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000494:pharmacology; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins; D009206:Myocardium / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; C405619:HIGD1A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D053829:Amyloid Precursor Protein Secretases