| International Session（Workshop）1(JSH・JSGE) |
| Thu. November 5th 9:40 - 12:00 Room 11: Portopia Hotel South Wing Topaz |
| Iron loss induce-mitophagy via mitochondrial ferritin suppresses hepatocellular carcinoma | |||
| Yuichi Hara1, Keisuke Hino1 | |||
| 1Department of Hepatology and Pancreatology, Kawasaki Medical School | |||
|
|||
|
|||
| Background and aim: Mitochondrial dysfunction plays a critical role in nonalcoholic steatohepatitis (NASH) development and subsequent progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial quality is controlled by selective removal of defective mitochondria through autophagy (mitophagy). An iron loss triggers mitophagy by a yet unknown mechanism and whether this could be used to improve mitochondrial function as a therapeutic strategy for HCC suppression has not been tested. Methods: The effect of iron chelator, deferiprone (DFP), on mitophagy was examined using Huh7 and HepG2 cells and NASH-related hepatocarcinogenic mouse models. Results: Iron loss induced by iron chelator, deferiprone suppressed NASH-related liver fibrosis and HCC development by inducing mitophagy. Deferiprone treatment increased expression of mitochondrial ferritin (FTMT). Silencing FTMT abrogated deferiprone-induced mitophagy and suppression of HCC. Specific protein 1 and its regulator hypoxia inducible factor 1 a were necessary for deferiprone-induced increase in FTMT. Deferiprone treatment resulted in localization of FTMT precursor on the mitochondrial outer membrane. FTMT specifically interacted with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone-induced mitophagy occurred selectively for depolarized mitochondria. Conclusion: These results provide a rationale for targeting mitophagic activation as a therapeutic strategy against NASH-related liver fibrosis and HCC. |
|||
|
Index Term 1: NASH Index Term 2: mitophagy |
|||
| Page Top | |||