title: The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation.
abstract: Higd-1a (hypoxia induced gene domain family-1a) is a mitochondrial inner membrane protein with a conformation of N-terminal outside-C-terminal outside and loop inside. There are four Higd genes, Higd-1a, -1b, -1c and -2a, in the mouse. Higd-1a and -2a are expressed primarily in the brain, heart, kidney and leukocytes. HIF (hypoxia-inducible factor) overexpression induced the endogenous expression and promoter activity of Higd-1a. Mutation of the HRE (hypoxia-response element) site at -32bp in the Higd-1a promoter reduced the promoter activity, suggesting that transcription of Higd-1a is regulated by binding of the transcription factor HIF to the HRE. Higd-1a promoted cell survival under hypoxia. RAW264.7 cells stably transfected with Higd-1a underwent less apoptosis than control cells in a hypoxic condition, and hypoxia-induced apoptosis was strongly enhanced when endogenous Higd-1a was silenced by siRNA. The survival effect of Higd-1a was completely abolished by deletion of the 26 N-terminal amino acids, and we showed that Higd-1a increased survival by inhibiting cytochrome C release and reducing the activities of caspases. However, expression of Bcl-2, Bax, Bad, and BNIP3 and translocation of AIF were unaffected under the same conditions. Higd-2a also enhanced cell survival under hypoxia. Cells transfected with Higd-2a underwent less apoptosis than control cells in hypoxic conditions, and hypoxia-induced apoptosis increased when endogenous Higd-2a was depleted. Together these observations indicate that Higd-1a is induced by hypoxia in a HIF-dependent manner and its anti-apoptotic effect results from inhibiting cytochrome C release and reducing caspase activities.
authors.affiliation: Department of Biology, BK21 Daedeok R&D Innopolis Bio Brain Center, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: An
authors.forename: Hyojung
authors.initials: H
authors.lastname: Shin
authors.forename: Sang-Geun
authors.initials: SG
authors.lastname: Jo
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jie-Oh
authors.initials: JO
authors.lastname: Lee
authors.forename: Sang-Gi
authors.initials: SG
authors.lastname: Paik
authors.forename: Hayyoung
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D004789:Enzyme Activation; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D004272:DNA, Mitochondrial; C497443:Hif1a protein, mouse; C512983:Hig1 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D045304:Cytochromes c; D020169:Caspases