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: Shigeki Sawada, Takao Kinjo, Shoko Makishi, Mariko Tomita, Akira Arasaki, Kunitoshi Iseki, Hisami Watanabe, Keiko Kobayashi, Hajime Sunakawa, Teruo Iwamasa, Naoki Mori
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 364 Issue 4 Pg. 937-44 (Dec 28 2007) ISSN: 1090-2104 [Electronic] United States
• PMID: 18273444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Amino Acid Transport Systems, Acidic
• Antiporters
• Calcium-Binding Proteins
• Organic Anion Transporters
• RNA, Small Interfering
• aspartate-glutamate carrier
• citrin
• Cytochromes c
• Caspases

Topics

• Amino Acid Transport Systems, Acidic (metabolism)
• Antiporters (metabolism)
• Apoptosis
• Calcium-Binding Proteins (genetics, metabolism)
• Caspases (metabolism)
• Cells, Cultured
• Citrullinemia (genetics, metabolism, pathology)
• Cytochromes c (metabolism)
• Down-Regulation (genetics)
• Hepatocytes (cytology, metabolism)
• Humans
• Mitochondria (metabolism)
• Organic Anion Transporters (genetics, metabolism)
• RNA, Small Interfering (genetics)