Iron loss triggers mitophagy through induction of mitochondrial ferritin. (25th September 2020)

• Record Type: Journal Article
• Authors: Hara, Yuichi; Yanatori, Izumi; Tanaka, Atsushi; Kishi, Fumio; Lemasters, John J; Nishina, Sohji; Sasaki, Kyo; Hino, Keisuke
• Is Part Of: EMBO reports. Volume 21:Number 11(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-09-25
• Subjects: hepatocellular carcinoma -- iron chelator -- mitochondria -- mitochondrial ferritin -- mitophagy; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202050202
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Iron loss induces mitochondrial ferritin via hypoxia inducible factor 1α‐specific protein 1 axis, and triggers mitophagy for the damaged mitochondria. Deferiprone, an iron chelator, increases the expression of mitochondrial ferritin (FTMT) through hypoxia inducible factor 1α‐specific protein 1 axis. FTMT specifically interacts with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone‐induced mitophagy occurs selectively for depolarized mitochondria. Deferiprone suppresses the development of hepatocellular carcinoma (HCC) in mice by inducing mitophagy. FTMT depletion in mice abrogates deferiprone‐induced mitophagy and suppression of HCC. Abstract : Iron loss induces mitochondrial ferritin via hypoxia inducible factor 1α‐specific protein 1 axis, and triggers mitophagy for the damaged mitochondria.