RRC ID 68151
Author Hara Y, Yanatori I, Tanaka A, Kishi F, Lemasters JJ, Nishina S, Sasaki K, Hino K.
Title Iron loss triggers mitophagy through induction of mitochondrial ferritin.
Journal EMBO Rep
Abstract 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 1α 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.
Volume 21(11)
Pages e50202
Published 2020-11-5
DOI 10.15252/embr.202050202
PMID 32975364
PMC PMC7645172
MeSH Animals Carcinoma, Hepatocellular* Ferritins / genetics Iron / metabolism Liver Neoplasms* Mice Mitochondrial Proteins / metabolism Mitophagy
IF 7.497
DNA material FTMT(wt)-GFP (RDB19183) FTMT(R82A)-GFP (RDB19184) FTMT(D57A)-GFP (RDB19185) FTMT(61-242)-GFP (RDB19186) FTMT(1-61)-GFP (RDB19187) FTH1-GFP (RDB19188) NCOA4-mCherry (RDB19189) NCOA4(I489A/W497A)-mCherry (RDB19190) PMP34-FTMT-GFP (RDB19191) pET32a-FTMT(61-242) (RDB19192) pGEX2T-NCOA4(382-522) (RDB19193) siRNA-resistant-FTMT-GFP (RDB19194)