title: Downregulation of citrin, a mitochondrial AGC, is associated with apoptosis of hepatocytes.
abstract: Citrin is a mitochondrial aspartate-glutamate carrier primarily expressed in liver. Adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin, and patients with this condition do not express citrin. We found apoptotic hepatocytes in one such patient. This finding prompted us to investigate the role of citrin in hepatocyte survival. Knockdown of citrin by a vector-based short-hairpin RNA technique reduced cell viability and induced apoptosis of a hepatocellular carcinoma cell line, Hep3B cells. Caspase-3/7 and caspase-9 were activated, and PARP was cleaved. Citrin knockdown also increased the expression of Bax and Bak, and reduced expression of Bcl-xL and Bcl-2. These alterations resulted in the release of cytochrome c from the mitochondria. Our results indicated that citrin downregulation induces apoptosis of hepatocytes through the mitochondrial death pathway, highlighting the importance of citrin in survival of hepatocytes and maintenance of liver function.
authors.affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 2 07 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sawada
authors.forename: Takao
authors.initials: T
authors.lastname: Kinjo
authors.forename: Shoko
authors.initials: S
authors.lastname: Makishi
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomita
authors.forename: Akira
authors.initials: A
authors.lastname: Arasaki
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Iseki
authors.forename: Hisami
authors.initials: H
authors.lastname: Watanabe
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Sunakawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Iwamasa
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism*; D017920:Antiporters / Q000378:metabolism*; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D020159:Citrullinemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D002135:Calcium-Binding Proteins; D027361:Organic Anion Transporters; D034741:RNA, Small Interfering; C051046:aspartate-glutamate carrier; C008822:citrin; D045304:Cytochromes c; D020169:Caspases