期刊
EMBO REPORTS
卷 21, 期 11, 页码 -出版社
WILEY
DOI: 10.15252/embr.202050202
关键词
hepatocellular carcinoma; iron chelator; mitochondria; mitochondrial ferritin; mitophagy
资金
- Japan Society for the Promotion of Science [26293179, 16K09384, 26870067/16K19047, 23870008]
- Research Program on Hepatitis from the Japan Agency for Medical Research and Development [18fk0210016 h0003]
- GSK Japan Research Grant
- Cell Science Research Foundation
- Uehara memorial Foundation
- Sumitomo Foundation
- Grants-in-Aid for Scientific Research [23870008, 16K09384, 26293179] Funding Source: KAKEN
Mitochondrial quality is controlled by the selective removal of damaged mitochondria through mitophagy. Mitophagy impairment is associated with aging and many pathological conditions. An iron loss induced by iron chelator triggers mitophagy by a yet unknown mechanism. This type of mitophagy may have therapeutic potential, since iron chelators are clinically used. Here, we aimed to clarify the mechanisms by which iron loss induces mitophagy. Deferiprone, an iron chelator, treatment resulted in the increased expression of mitochondrial ferritin (FTMT) and the localization of FTMT precursor on the mitochondrial outer membrane. Specific protein 1 and its regulator hypoxia-inducible factor 1 alpha were necessary for deferiprone-induced increase in FTMT. FTMT specifically interacted with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone-induced mitophagy occurred selectively for depolarized mitochondria. Additionally, deferiprone suppressed the development of hepatocellular carcinoma (HCC) in mice by inducing mitophagy. Silencing FTMT abrogated deferiprone-induced mitophagy and suppression of HCC. These results demonstrate the mechanisms by which iron loss induces mitophagy and provide a rationale for targeting mitophagic activation as a therapeutic strategy.
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