Abstract:Mitochondrial ferritin (FtMt) is an iron storage protein belonging to the ferritin family but, unlike the cytosolic ferritin, it has an iron-unrelated restricted tissue expression. FtMt appears to be preferentially expressed in cell types characterized by high metabolic activity and oxygen consumption, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. The human gene (FTMT) is intronless and its promoter region has not been described yet. To analyze the regulatory mechanisms con… Show more
“…Two‐sample t ‐test was used for statistical analysis. ** P < 0.01. GA representation of the reported transcription factors for the mitochondrial ferritin promoter (Guaraldo et al , 2016). The locations of putative binding sites for transcription are boxed: Positive transcription factors (SP1, CREB, and YY1) are in red, while negative transcription factors (GATA2, FoxA1, and C/EBPβ) are in blue.Source data are available online for this figure.…”
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.
“…Two‐sample t ‐test was used for statistical analysis. ** P < 0.01. GA representation of the reported transcription factors for the mitochondrial ferritin promoter (Guaraldo et al , 2016). The locations of putative binding sites for transcription are boxed: Positive transcription factors (SP1, CREB, and YY1) are in red, while negative transcription factors (GATA2, FoxA1, and C/EBPβ) are in blue.Source data are available online for this figure.…”
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.
“…We found that Roflumilast could phosphorylate CREB to up-regulate the level of FtMt, and the promoter region of FtMt was reported to harbor the binding site of CREB [ 17 ], which implicated that the increased expression of FtMt in ovarian cancer was attributed to the transcription of CREB. To confirm the binding site of CREB within FtMt promoter region in ovarian cancer, the luciferase reporter assays were performed by using Calyculin A which was demonstrated to be the activator of CREB.…”
The abrogation of cAMP generation by overexpression of PDE isoforms promotes the inflammatory pathology, and the PDE inhibitors have showed the potential anti-inflammation effects in clinical. However, the function of PDE inhibitors in cancer treatment remains unclear. We here investigated the role of PDE4 inhibitor Roflumilast in the treatment of ovarian cancer. We found that Roflumilast could effectively inhibit the proliferation, and induce apoptosis and cell cycle arrest in two ovarian cancer cell lines OVCAR3 and SKOV3. Meanwhile, the cAMP/PKA/CREB signals was activated by Roflumilast, which was accompanied by the up-regulation of mitochondrial ferritin (FtMt) level. Interestingly, forced expression of FtMt in ovarian cancer enhanced the apoptosis and inhibited tumor growth and the PKA inhibitor H89 and knockdown of CREB significantly repressed the expression of FtMt to restore the tumor proliferation and inhibit apoptosis. In addition, we found that Roflumilast-induced phosphorylated CREB directly promoted transcription of FtMt, indicating that Roflumilast up-regulated the expression of FtMt in ovarian cancer via cAMP/PKA/CREB signals. The anti-tumor role of Roflumilast in vivo was also demonstrated, the treatment of roflumilast effectively inhibited tumor proliferation and elevated the FtMt expression to restrict the tumor growth via the activation of cAMP/PKA/CREB signals in ovarian cancer.
“…SIRT3 loss increases ROS production, bringing about elevated IRP1 binding to IREs and increased TfR-1 expression as a consequence [70]. Mitochondrial ferritin (FTMT) appears regulated by a complex mechanism involving epigenetic events, such as histone de-acetylases recruitment and GC islands accumulation at its promoter, and interplay between transcription factors, such as CREB, SP1, and YY1 [71]. Nuclear factor erythroid 2-like 2 (NRF2) and myeloid zinc finger-1 (MZF-1) could impact cancer cell growth by transcriptionally regulating FPN, FTH, and FTL expression in prostate and breast cancer [72].…”
Section: Iron and Epigenetic Regulation In Cancermentioning
Demanded as an essential trace element that supports cell growth and basic functions, iron can be harmful and cancerogenic though. By exchanging between its different oxidized forms, iron overload induces free radical formation, lipid peroxidation, DNA, and protein damages, leading to carcinogenesis or ferroptosis. Iron also plays profound roles in modulating tumor microenvironment and metastasis, maintaining genomic stability and controlling epigenetics. in order to meet the high requirement of iron, neoplastic cells have remodeled iron metabolism pathways, including acquisition, storage, and efflux, which makes manipulating iron homeostasis a considerable approach for cancer therapy. Several iron chelators and iron oxide nanoparticles (IONPs) has recently been developed for cancer intervention and presented considerable effects. This review summarizes some latest findings about iron metabolism function and regulation mechanism in cancer and the application of iron chelators and IONPs in cancer diagnosis and therapy.
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