|
1
|
Zhang T, Liu Q, Chen Q, Wu H. Iron regulatory protein two facilitates ferritinophagy and DNA damage/repair through guiding ATG9A trafficking. J Biol Chem 2024; 300:107767. [PMID: 39276939 PMCID: PMC11490887 DOI: 10.1016/j.jbc.2024.107767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 07/17/2024] [Accepted: 08/25/2024] [Indexed: 09/17/2024] Open
Abstract
Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with disease pathogenesis. IRPs-IREs system is located at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycling, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2-depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.
Collapse
Affiliation(s)
- Ting Zhang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China
| | - Qian Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China
| | - Quan Chen
- State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China; Hubei Hongshan Laboratory, Wuhan, Hubei, China.
| |
Collapse
|
|
2
|
Yao Z, Jia F, Wang S, Jiao Q, Du X, Chen X, Jiang H. The involvement of IRP2-induced ferroptosis through the p53-SLC7A11-ALOX12 pathway in Parkinson's disease. Free Radic Biol Med 2024; 222:386-396. [PMID: 38936518 DOI: 10.1016/j.freeradbiomed.2024.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/17/2024] [Accepted: 06/24/2024] [Indexed: 06/29/2024]
Abstract
Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.
Collapse
Affiliation(s)
- Zhengyang Yao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Fengju Jia
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Shuhua Wang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines, Physiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266500, China.
| |
Collapse
|
|
3
|
Hacioglu C, Tuncer C. Boric acid Increases Susceptibility to Chemotherapy by Targeting the Ferritinophagy Signaling Pathway in TMZ Resistant Glioblastoma Cells. Biol Trace Elem Res 2024; 202:3574-3587. [PMID: 37906374 DOI: 10.1007/s12011-023-03930-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/22/2023] [Indexed: 11/02/2023]
Abstract
Glioblastoma (GBM) is a common and highly lethal form of brain cancer. Temozolomide (TMZ) is the primary chemotherapy used for GBM, but it has limited effectiveness, with about half of the patients developing resistance. Iron regulatory proteins (IRPs) modulate genes involved in iron metabolism, while the nuclear receptor coactivator 4 (NCOA4) controls iron metabolism through a process called ferritinophagy. In this study, we investigated whether boric acid increases chemosensitivity mediated by ferritinophagy via the NCOA4 and IRP2 signaling pathways in TMZ-resistant GBM cells. First, we generated TMZ-resistant GBM cells (A172-R and T98G-R cells). Next, we investigated the effects of boric acid on cell viability, proliferation, cell cycle, and cell morphology in these cells. Additionally, following boric acid treatment, we analyzed the expression and protein levels of various biochemical markers in these cells. Boric acid treatment in A172-R and T98G-R cells suppressed cell viability and proliferation, arrested these cells in the G1/G0 cell cycle, and induced morphological differences. Boric acid increased NCOA4, IRP2, iron, and malondialdehyde (MDA) levels in A172-R and T98G-R cells, while glutathione (GSH) and glutathione peroxidase 4 (GPx4) levels decreased. Moreover, boric acid treatment increased intracellular iron levels and lipid peroxidation by inducing NCOA4 and IRP2 expression levels in TMZ-resistant cells. According to our results, boric acid may regulate chemosensitivity in A172-R and T98G-R cells mediated by NCOA4 and IRP2. In conclusion, the manipulative effects of boric acid on the ferritinophagy pathway hold the potential to sensitize TMZ-resistant GBM cells to chemotherapy.
Collapse
Affiliation(s)
- Ceyhan Hacioglu
- Faculty of Pharmacy, Department of Biochemistry, Düzce University, Düzce, Turkey.
- Faculty of Medicine, Department of Medical Biochemistry, Düzce University, Düzce, Turkey.
| | - Cengiz Tuncer
- Faculty of Medicine, Department of Neurosurgery, Düzce University, Düzce, Turkey
| |
Collapse
|
|
4
|
Zhou X, Wang Y, Li X, Zhou J, Yang W, Wang X, Jiao S, Zuo W, You Z, Ying W, Wu C, Bao J. O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells. Redox Biol 2024; 73:103182. [PMID: 38744192 PMCID: PMC11103954 DOI: 10.1016/j.redox.2024.103182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/16/2024] Open
Abstract
Ferroptosis is an iron-dependent programmed cell death (PCD) enforced by lipid peroxidation accumulation. Transferrin receptor (TFRC), one of the signature proteins of ferroptosis, is abundantly expressed in hepatocellular carcinoma (HCC). However, post-translational modification (PTM) of TFRC and the underlying mechanisms for ferroptosis regulation remain less understood. In this study, we found that TFRC undergoes O-GlcNAcylation, influencing Erastin-induced ferroptosis sensitivity in hepatocytes. Further mechanistic studies found that Erastin can trigger de-O-GlcNAcylation of TFRC at serine 687 (Ser687), which diminishes the binding of ubiquitin E3 ligase membrane-associated RING-CH8 (MARCH8) and decreases polyubiquitination on lysine 665 (Lys665), thereby enhancing TFRC stability that favors labile iron accumulation. Therefore, our findings report O-GlcNAcylation on an important regulatory protein of ferroptosis and reveal an intriguing mechanism by which HCC ferroptosis is controlled by an iron metabolism pathway.
Collapse
Affiliation(s)
- Xunyu Zhou
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Yida Wang
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Xiaoyu Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Jing Zhou
- West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wanyi Yang
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Xin Wang
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Sitong Jiao
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Weibo Zuo
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Ziming You
- School of Life Sciences, Sichuan University, Chengdu, 610041, China
| | - Wantao Ying
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Chuanfang Wu
- School of Life Sciences, Sichuan University, Chengdu, 610041, China.
| | - Jinku Bao
- School of Life Sciences, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
5
|
Nadimpalli HP, Katsioudi G, Arpa ES, Chikhaoui L, Arpat AB, Liechti A, Palais G, Tessmer C, Hofmann I, Galy B, Gatfield D. Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms. Genome Biol 2024; 25:128. [PMID: 38773499 PMCID: PMC11106963 DOI: 10.1186/s13059-024-03270-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/09/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Cellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in the liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver. RESULTS We uncover high-amplitude diurnal oscillations in the regulation of key IRE-containing transcripts in the liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light-dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this timepoint still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic. CONCLUSIONS Our findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.
Collapse
Affiliation(s)
| | - Georgia Katsioudi
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
| | - Enes Salih Arpa
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
| | - Lies Chikhaoui
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
| | - Alaaddin Bulak Arpat
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
| | - Angelica Liechti
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
| | - Gaël Palais
- German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
| | - Claudia Tessmer
- German Cancer Research Center (DKFZ), Core Facility Antibodies, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
| | - Ilse Hofmann
- German Cancer Research Center (DKFZ), Core Facility Antibodies, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
| | - Bruno Galy
- German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
| | - David Gatfield
- Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.
| |
Collapse
|
|
6
|
Zhang DL, Ollivierre H, Rouault TA. Using Biotinylated Iron-Responsive Element to Analyze the Activity of Iron Regulatory Proteins. Int J Mol Sci 2024; 25:4852. [PMID: 38732071 PMCID: PMC11084215 DOI: 10.3390/ijms25094852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 04/26/2024] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
Iron regulatory proteins (IRP1 and IRP2) are the master regulators of mammalian iron homeostasis. They bind to the iron-responsive elements (IREs) of the transcripts of iron-related genes to regulate their expression, thereby maintaining cellular iron availability. The primary method to measure the IRE-binding activity of IRPs is the electrophoresis mobility shift assay (EMSA). This method is particularly useful for evaluating IRP1 activity, since IRP1 is a bifunctional enzyme and its protein levels remain similar during conversion between the IRE-binding protein and cytosolic aconitase forms. Here, we exploited a method of using a biotinylated-IRE probe to separate IRE-binding IRPs followed by immunoblotting to analyze the IRE-binding activity. This method allows for the successful measurement of IRP activity in cultured cells and mouse tissues under various iron conditions. By separating IRE-binding IRPs from the rest of the lysates, this method increases the specificity of IRP antibodies and verifies whether a band represents an IRP, thereby revealing some previously unrecognized information about IRPs. With this method, we showed that the S711-phosphorylated IRP1 was found only in the IRE-binding form in PMA-treated Hep3B cells. Second, we found a truncated IRE-binding IRP2 isoform that is generated by proteolytic cleavage on sites in the 73aa insert region of the IRP2 protein. Third, we found that higher levels of SDS, compared to 1-2% SDS in regular loading buffer, could dramatically increase the band intensity of IRPs in immunoblots, especially in HL-60 cells. Fourth, we found that the addition of SDS or LDS to cell lysates activated protein degradation at 37 °C or room temperature, especially in HL-60 cell lysates. As this method is more practical, sensitive, and cost-effective, we believe that its application will enhance future research on iron regulation and metabolism.
Collapse
Affiliation(s)
| | | | - Tracey A. Rouault
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; (D.-L.Z.); (H.O.)
| |
Collapse
|
|
7
|
Terzi EM, Possemato R. Iron, Copper, and Selenium: Cancer's Thing for Redox Bling. Cold Spring Harb Perspect Med 2024; 14:a041545. [PMID: 37932129 PMCID: PMC10982729 DOI: 10.1101/cshperspect.a041545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
Abstract
Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.
Collapse
Affiliation(s)
- Erdem M Terzi
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, New York 10016, USA
| | - Richard Possemato
- Department of Pathology, New York University Grossman School of Medicine, New York, New York 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, New York 10016, USA
| |
Collapse
|
|
8
|
Liu Q, Wang F, Chen Y, Cui H, Wu H. A regulatory module comprising G3BP1-FBXL5-IRP2 axis determines sodium arsenite-induced ferroptosis. JOURNAL OF HAZARDOUS MATERIALS 2024; 465:133038. [PMID: 38118197 DOI: 10.1016/j.jhazmat.2023.133038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/26/2023] [Accepted: 11/17/2023] [Indexed: 12/22/2023]
Abstract
Arsenic contamination is extremely threatening to the global public health. It was reported that sodium arsenite exposure induces serious kidney injury. However, the underlying mechanism is unclear. Ferroptosis is a newly characterized form of iron-dependent programmed cell death, which is implicated in the pathogenesis of various human diseases, including kidney injury. The lethal accumulation of iron-catalyzed lipid peroxidation is the fundamental biochemical characteristic of ferroptosis. Herein we report that sodium arsenite exposure initiates ferroptosis in mammalian HEK293, MEF and HT1080 cells, and induces ferroptosis-associated acute kidney injury in mice. RNA-binding protein G3BP1, the switch component of stress granules, is indispensable for sodium arsenite-induced ferroptosis in a stress granule-independent manner. Mechanistically, G3BP1 stabilizes IRP2, the master regulator of cellular iron homeostasis, through binding to and suppressing the translation of FBXL5 mRNA, which encodes the E3 ligase component to mediate IRP2 ubiquitination and proteasomal degradation. Sodium arsenite intoxication expedites this G3BP1-FBXL5-IRP2 axis and elevates cellular labile free iron, which is responsible for sodium arsenite exposure-induced lipid peroxidation and ferroptotic cell death. In summary, this study highlights a regulatory module comprising G3BP1-FBXL5-IRP2 axis in determining sodium arsenite-induced ferroptosis and ferroptosis-associated acute kidney injury in mice.
Collapse
Affiliation(s)
- Qian Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
| | - Fengli Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yingxian Chen
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
| | - Hengkang Cui
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan, Hubei 430070, China.
| |
Collapse
|
|
9
|
Yang J, Du C, Li Y, Liu R, Jing C, Xie J, Wang J. Contrasting Iron Metabolism in Undifferentiated Versus Differentiated MO3.13 Oligodendrocytes via IL-1β-Induced Iron Regulatory Protein 1. Neurochem Res 2024; 49:466-476. [PMID: 37917337 DOI: 10.1007/s11064-023-04047-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 09/28/2023] [Accepted: 10/14/2023] [Indexed: 11/04/2023]
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of iron in the substantia nigra. While iron accumulation and inflammation are implicated in PD pathogenesis, their impact on oligodendrocytes, the brain's myelin-forming cells, remains elusive. This study investigated the influence of interleukin-1β (IL-1β), an elevated proinflammatory cytokine in PD, on iron-related proteins in MO3.13 oligodendrocytes. We found that IL-1β treatment in undifferentiated MO3.13 oligodendrocytes increased iron regulatory protein 1 and transferrin receptor 1 (TfR1) expression while decreasing ferroportin 1 (FPN1) expression. Consequently, iron uptake was enhanced, and iron release was reduced, leading to intracellular iron accumulation. Conversely, IL-1β treatment in differentiated MO3.13 oligodendrocytes exhibited the opposite effect, with decreased TfR1 expression, increased FPN1 expression, and reduced iron uptake. These findings suggest that IL-1β-induced dysregulation of iron metabolism in oligodendrocytes may contribute to the pathological processes observed in PD. IL-1β can increase the iron content in undifferentiated oligodendrocytes, thus facilitating the differentiation of undifferentiated MO3.13 oligodendrocytes. In differentiated oligodendrocytes, IL-1β may facilitate iron release, providing a potential source of iron for neighboring dopaminergic neurons, thereby initiating a cascade of deleterious events. This study provides valuable insights into the intricate interplay between inflammation, abnormal iron accumulation, and oligodendrocyte dysfunction in PD. Targeting the IL-1β-mediated alterations in iron metabolism may hold therapeutic potential for mitigating neurodegeneration and preserving dopaminergic function in PD.
Collapse
Affiliation(s)
- Jiahua Yang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Chenchen Du
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
- Institute of Senior Care and Art, Guangdong Vocational College of Hotel Management, Dongguan, China
| | - Yinghui Li
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Rong Liu
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Cuiting Jing
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Junxia Xie
- Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China
| | - Jun Wang
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
- Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China.
| |
Collapse
|
|
10
|
Ghatpande N, Harrer A, Azoulay-Botzer B, Guttmann-Raviv N, Bhushan S, Meinhardt A, Meyron-Holtz EG. Iron regulatory proteins 1 and 2 have opposing roles in regulating inflammation in bacterial orchitis. JCI Insight 2024; 9:e175845. [PMID: 38301068 PMCID: PMC11143929 DOI: 10.1172/jci.insight.175845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 01/30/2024] [Indexed: 02/03/2024] Open
Abstract
Acute bacterial orchitis (AO) is a prevalent cause of intrascrotal inflammation, often resulting in sub- or infertility. A frequent cause eliciting AO is uropathogenic Escherichia coli (UPEC), a gram negative pathovar, characterized by the expression of various iron acquisition systems to survive in a low-iron environment. On the host side, iron is tightly regulated by iron regulatory proteins 1 and 2 (IRP1 and -2) and these factors are reported to play a role in testicular and immune cell function; however, their precise role remains unclear. Here, we showed in a mouse model of UPEC-induced orchitis that the absence of IRP1 results in less testicular damage and a reduced immune response. Compared with infected wild-type (WT) mice, testes of UPEC-infected Irp1-/- mice showed impaired ERK signaling. Conversely, IRP2 deletion led to a stronger inflammatory response. Notably, differences in immune cell infiltrations were observed among the different genotypes. In contrast with WT and Irp2-/- mice, no increase in monocytes and neutrophils was detected in testes of Irp1-/- mice upon UPEC infection. Interestingly, in Irp1-/- UPEC-infected testes, we observed an increase in a subpopulation of macrophages (F4/80+CD206+) associated with antiinflammatory and wound-healing activities compared with WT. These findings suggest that IRP1 deletion may protect against UPEC-induced inflammation by modulating ERK signaling and dampening the immune response.
Collapse
Affiliation(s)
- Niraj Ghatpande
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel
| | - Aileen Harrer
- Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Bar Azoulay-Botzer
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel
| | - Noga Guttmann-Raviv
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel
| | - Sudhanshu Bhushan
- Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Andreas Meinhardt
- Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Esther G. Meyron-Holtz
- Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, Haifa, Israel
| |
Collapse
|
|
11
|
Zhu J, Wang Y, Rivett A, Yang G. H 2S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions. Cell Signal 2023; 110:110826. [PMID: 37487913 DOI: 10.1016/j.cellsig.2023.110826] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 07/26/2023]
Abstract
Either H2S or iron is essential for cellular processes. Abnormal metabolism of H2S and iron has increased risk for cardiovascular diseases. The aim of the present study is to examine the mutual interplay of iron and H2S signals in regulation of vascular smooth muscle cell (SMC) functions. Here we found that deficiency of cystathionine gamma-lyase (CSE, a major H2S-producing enzyme in vascular system) induced but NaHS (a H2S donor) administration attenuated iron accumulation in aortic tissues from angiotensin II-infused mice. In vitro, iron overload induced labile iron levels, promoted cell proliferation, disrupted F-actin filaments, and inhibited protein expressions of SMC-specific markers (αSMA and calponin) more significantly in SMCs from CSE knockout mice (KO-SMCs) than the cells from wild-type mice (WT-SMCs), which could be reversed by exogenously applied NaHS. In contrast, KO-SMCs were more vulnerable to iron starvation-induced cell death. Either iron overload or NaHS did not affect elastin level and gelatinolytic activity. We further found that H2S induced more aconitase activity of iron regulatory protein 1 (IRP1) but inhibited its RNA binding activity accompanied with increased protein levels of ferritin and ferriportin, which would contribute to the lower level of labile iron level inside the cells. In addition, iron was able to suppress CSE-derived H2S generation, while iron also non-enzymatically induced H2S release from cysteine. This study reveals the mutual interaction between iron and H2S signals in regulating SMC phenotypes and functions; CSE/H2S system would be a target for preventing iron metabolic disorder-related vascular diseases.
Collapse
Affiliation(s)
- Jiechun Zhu
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Yuehong Wang
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Alexis Rivett
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Guangdong Yang
- School of Natural Sciences, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
| |
Collapse
|
|
12
|
Zhang Z, Jiang W, Zhang C, Yin Y, Mu N, Wang Y, Yu L, Ma H. Frataxin inhibits the sensitivity of the myocardium to ferroptosis by regulating iron homeostasis. Free Radic Biol Med 2023; 205:305-317. [PMID: 37343689 DOI: 10.1016/j.freeradbiomed.2023.06.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 06/23/2023]
Abstract
RATIONALE Myocardial ischemia/reperfusion (I/R) injury is characterized by cell death via various cellular mechanisms upon reperfusion. As a new type of cell death, ferroptosis provides new opportunities to reduce myocardial cell death. Ferroptosis is known to be more active during reperfusion than ischemia. However, the mechanisms regulating ferroptosis during ischemia and reperfusion remain largely unknown. METHODS The contribution of ferroptosis in ischemic and reperfused myocardium were detected by administered of Fer-1, a ferroptosis inhibitor to C57BL/6 mice, followed by left anterior descending (LAD) ligation surgery. Ferroptosis was evaluated by measurement of cell viability, ptgs2 mRNA level, iron production, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. H9C2 cells were exposed to hypoxia/reoxygenation to mimic in vivo I/R. We used LC-MS/MS to identify potential E3 ligases that interacted with frataxin in heart tissue. Cardiac-specific overexpression of frataxin in whole heart was achieved by intracardiac injection of frataxin, carried by adeno-associated virus serotype 9 (AAV9) containing cardiac troponin T (cTnT) promoter. RESULTS We showed that regulators of iron metabolism, especially iron regulatory protein activity, were increased in the ischemic myocardium or hypoxia cardiomyocytes. In addition, we found that frataxin, which is involved in iron metabolism, is differentially expressed in the ischemic and reperfused myocardium and involved in the regulation of cardiomyocytes ferroptosis. Furthermore, we identified an E3 ligase, NHL repeat-containing 1 (NHLRC1), that mediates frataxin ubiquitination degradation. Cardiac-specific overexpression of frataxin ameliorated myocardial I/R injury through ferroptosis inhibition. CONCLUSIONS Through a multi-level study from molecule to animal model, these findings uncover the key role of frataxin in inhibiting cardiomyocyte ferroptosis and provide new strategies and perspectives for the treatment of myocardial I/R injury.
Collapse
Affiliation(s)
- Zihui Zhang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Wenhua Jiang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Chan Zhang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Nan Mu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Yishi Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Lu Yu
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
| | - Heng Ma
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China; Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China.
| |
Collapse
|
|
13
|
Fahoum L, Belisowski S, Ghatpande N, Guttmann-Raviv N, Zhang W, Li K, Tong WH, Nyska A, Waterman M, Weisshof R, Zuckerman A, Meyron-Holtz E. Iron Regulatory Protein 1 is Required for the Propagation of Inflammation in Inflammatory Bowel Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.27.525690. [PMID: 36789413 PMCID: PMC9928023 DOI: 10.1101/2023.01.27.525690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Objective Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. Design This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. Results We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. Conclusion These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.
Collapse
Affiliation(s)
- L. Fahoum
- Laboratory of Molecular Nutrition, Department of Biotechnology and Food Engineering, Technion– Israel Institute of Technology, Haifa, Israel
| | - S. Belisowski
- Laboratory of Molecular Nutrition, Department of Biotechnology and Food Engineering, Technion– Israel Institute of Technology, Haifa, Israel
| | - N. Ghatpande
- Laboratory of Molecular Nutrition, Department of Biotechnology and Food Engineering, Technion– Israel Institute of Technology, Haifa, Israel
| | - N. Guttmann-Raviv
- Laboratory of Molecular Nutrition, Department of Biotechnology and Food Engineering, Technion– Israel Institute of Technology, Haifa, Israel
| | - W. Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - K. Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - W-H. Tong
- Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA
| | - A. Nyska
- Tel Aviv University and Consultant in Toxicologic Pathology, Tel Aviv, Israel
| | - M. Waterman
- Rambam / Technion– Israel Institute of Technology, Haifa, Israel
| | - R. Weisshof
- Rambam / Technion– Israel Institute of Technology, Haifa, Israel
| | | | - E.G. Meyron-Holtz
- Laboratory of Molecular Nutrition, Department of Biotechnology and Food Engineering, Technion– Israel Institute of Technology, Haifa, Israel
| |
Collapse
|
|
14
|
Cardona CJ, Montgomery MR. Iron regulatory proteins: players or pawns in ferroptosis and cancer? Front Mol Biosci 2023; 10:1229710. [PMID: 37457833 PMCID: PMC10340119 DOI: 10.3389/fmolb.2023.1229710] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023] Open
Abstract
Cells require iron for essential functions like energy production and signaling. However, iron can also engage in free radical formation and promote cell proliferation thereby contributing to both tumor initiation and growth. Thus, the amount of iron within the body and in individual cells is tightly regulated. At the cellular level, iron homeostasis is maintained post-transcriptionally by iron regulatory proteins (IRPs). Ferroptosis is an iron-dependent form of programmed cell death with vast chemotherapeutic potential, yet while IRP-dependent targets have established roles in ferroptosis, our understanding of the contributions of IRPs themselves is still in its infancy. In this review, we present the growing circumstantial evidence suggesting that IRPs play critical roles in the adaptive response to ferroptosis and ferroptotic cell death and describe how this knowledge can be leveraged to target neoplastic iron dysregulation more effectively.
Collapse
|
|
15
|
Pauleta SR, Grazina R, Carepo MS, Moura JJ, Moura I. Iron-sulfur clusters – functions of an ancient metal site. COMPREHENSIVE INORGANIC CHEMISTRY III 2023:105-173. [DOI: 10.1016/b978-0-12-823144-9.00116-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
16
|
Lee D, Son E, Kim YH. Transferrin-mediated increase of labile iron Pool following simulated ischemia causes lipid peroxidation during the early phase of reperfusion. Free Radic Res 2022; 56:713-729. [PMID: 36794395 DOI: 10.1080/10715762.2023.2169683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Heart ischemia/reperfusion (I/R) injury is related to iron content. However, the occurrence and mechanism of changes in labile iron pool (LIP) during I/R is debatable. Moreover, the identity of the iron form dominant in LIP during I/R is unclear. Herein, we measured changes of LIP during simulated ischemia (SI) and reperfusion (SR), in which ischemia was simulated in vitro with lactic acidosis and hypoxia. Total LIP did not change in lactic acidosis, whereas LIP, especially Fe3+, increased in hypoxia. Under SI, accompanied by hypoxia with acidosis, both Fe2+ and Fe3+ were significantly increased. Increased total LIP was maintained at 1 h post-SR. However, the Fe2+ and Fe3+ portion was changed. The increased Fe2+ was decreased, and conversely the Fe3+ was increased. BODIPY oxidized signal increased and through the time-course these changes correlated with blebbing of cell membrane and SR-induced LDH release. These data suggested lipid peroxidation occurred via Fenton's reaction. The experiments using bafilomycin A1 and zinc protoporphyrin suggested no role of ferritinophagy or heme oxidation in the increase of LIP during SI. The extracellular source, transferrin assessed using serum transferrin bound iron (TBI) saturation showed that the depletion of TBI reduced SR-induced cell damages and additive saturation of TBI accelerated SR-induced lipid peroxidation. Furthermore, Apo-Tf dramatically blocked the increase of LIP and SR-induced damages. In conclusion, Tf-mediated iron induces the increase of LIP during SI, and it causes Fenton reaction-mediated lipid peroxidation during the early phase of SR.
Collapse
Affiliation(s)
- Dongju Lee
- Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-medical Institute of Technology, University of Ulsan, Songpa-gu, Korea.,Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan, Songpa-gu, Korea
| | - Euncheol Son
- Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-medical Institute of Technology, University of Ulsan, Songpa-gu, Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-Hoon Kim
- Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-medical Institute of Technology, University of Ulsan, Songpa-gu, Korea
| |
Collapse
|
|
17
|
QU L, HE X, TANG Q, FAN X, LIU J, LIN A. Iron metabolism, ferroptosis, and lncRNA in cancer: knowns and unknowns. J Zhejiang Univ Sci B 2022; 23:844-862. [PMID: 36226538 PMCID: PMC9561407 DOI: 10.1631/jzus.b2200194] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation. As an essential trace element, iron is vital for many biological processes. Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation. Ferroptosis, a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs), is a promising therapeutic target for therapy-resistant cancers. Previous studies have reported that long noncoding RNA (lncRNA) is a group of critical regulators involved in modulating cell metabolism, proliferation, apoptosis, and ferroptosis. In this review, we summarize the associations among iron metabolism, ferroptosis, and ferroptosis-related lncRNA in tumorigenesis. This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.
Collapse
Affiliation(s)
- Lei QU
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Xinyu HE
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Qian TANG
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining314400, China,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou310006, China,College of Medicine and Veterinary Medicine, the University of Edinburgh, EdinburghEH16 4SB, UK,Biomedical and Health Translational Research Center of Zhejiang Province, Haining314400, China
| | - Xiao FAN
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Jian LIU
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining314400, China,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou310006, China,College of Medicine and Veterinary Medicine, the University of Edinburgh, EdinburghEH16 4SB, UK,Biomedical and Health Translational Research Center of Zhejiang Province, Haining314400, China,Jian LIU,
| | - Aifu LIN
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China,Breast Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China,International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu322000, China,ZJU-QILU Joint Research Institute, Hangzhou310058, China,Aifu LIN,
| |
Collapse
|
|
18
|
Yang Y, Wang X, Xiao A, Han J, Wang Z, Wen M. Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer’s disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway. Front Aging Neurosci 2022; 14:998292. [PMID: 36118706 PMCID: PMC9475074 DOI: 10.3389/fnagi.2022.998292] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
Sleep deprivation (SD) is one of the main risk factors for Alzheimer’s disease (AD), but the underlying mechanism is still unclear. Ketogenic diet (KD) has been shown widely neuroprotective effects but less known about its effect on SD-induced AD. In the present study, a continuous 21 days SD mouse model with or without KD was established. The changes of cognitive function, pathological hallmarks of AD, ferroptosis, and intracellular signal pathways in mice were detected by Morris water maze, ThS staining, diaminobenzidine (DAB)-enhanced Perls’ stain, antioxidant assay, immuno-histochemistry, and western blot. The results showed that KD can prevent the cognitive deficiency, amyloid deposition and hyperphosphorylated tau induced by chronic SD. Analysis of ferroptosis revealed that KD can inhibit iron dyshomeostasis by down-regulating the expression of TfR1 and DMT1 and up-regulating the expression of FTH1, FPN1. Meanwhile, KD alleviated oxidative stress with elevated xCT/GPX4 axis, FSP1 and reduced MDA. In addition, KD could promote neuronal repair by enhancing BDNF and DCX. Further studies demonstrated that KD activated Sirt1/Nrf2 signaling pathway in the hippocampus in SD-exposed mice. Our finding firstly suggested that KD could prevent chronic SD-induced AD by inhibiting ferroptosis and improving the neuronal repair ability via Sirt1/Nrf2 signaling pathway.
Collapse
|
|
19
|
Zhu T, Xiao Z, Yuan H, Tian H, Chen T, Chen Q, Chen M, Yang J, Zhou Q, Guo W, Xue K, Xia M, Bao J, Yang C, Duan H, Wang H, Huang Z, Liu C, Zhou J. ACO1 and IREB2 downregulation confer poor prognosis and correlate with autophagy-related ferroptosis and immune infiltration in KIRC. Front Oncol 2022; 12:929838. [PMID: 36059676 PMCID: PMC9428356 DOI: 10.3389/fonc.2022.929838] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background ACO1 and IREB2 are two homologous cytosolic regulatory proteins, which sense iron levels and change iron metabolism–linked molecules. These two genes were noticeably decreased in kidney renal clear cell carcinoma (KIRC), which confer poor survival. Meanwhile, there is a paucity of information about the mechanisms and clinical significance of ACO1 and IREB2 downregulation in renal cancers. Methods The expression profiles of ACO1 and IREB2 were assessed using multiple public data sets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify cohorts for comparison. Patient survival outcomes were evaluated using the Kaplan–Meier plotter, a meta-analysis tool. The correlations of ACO1 and IREB2 with ferroptosis were further evaluated in The Cancer Genome Atlas (TCGA)–KIRC database. Tumor immune infiltration was analyzed using the CIBERSORT, TIMER, and GEPIA data resources. ACO1 antagonist sodium oxalomalate (OMA) and IREB2 inhibitor sodium nitroprusside (SNP) was used to treat renal cancer ACHN cells together with sorafenib. Results KIRC patients with low ACO1 or IREB2 contents exhibited a remarkably worse survival rate in contrast with those with high expression in Kaplan–Meier survival analyses. Meanwhile, ACO1 and IREB2 regulate autophagy-linked ferroptosis along with immune cell invasion in the tumor microenvironment in KIRC patients. Blocking the activation of these two genes by their inhibitors OMA and SNP ameliorated sorafenib-triggered cell death, supporting that ACO1 and IREB2 could be participated in its cytotoxic influence on renal cancer cells. Conclusion ACO1 and IREB2 downregulation in renal cancers were correlated with cancer aggressiveness, cellular iron homeostasis, cytotoxic immune cell infiltration, and patient survival outcomes. Our research is integral to verify the possible significance of ACO1 and IREB2 contents as a powerful signature for targeted treatment or novel immunotherapy in clinical settings.
Collapse
Affiliation(s)
- Ting Zhu
- Department of Laboratory Medicine, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Zhuoyu Xiao
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Haoyu Yuan
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Hu Tian
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Taoyi Chen
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Qi Chen
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Mingkun Chen
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Jiankun Yang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Qizhao Zhou
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Wenbin Guo
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Kangyi Xue
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Ming Xia
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Jiming Bao
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Cheng Yang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Haifeng Duan
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Hongyi Wang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Zhipeng Huang
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Cundong Liu
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Junhao Zhou, ; Cundong Liu,
| | - Junhao Zhou
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Junhao Zhou, ; Cundong Liu,
| |
Collapse
|
|
20
|
Targeting ferroptosis as a vulnerability in pulmonary diseases. Cell Death Dis 2022; 13:649. [PMID: 35882850 PMCID: PMC9315842 DOI: 10.1038/s41419-022-05070-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 01/21/2023]
Abstract
Ferroptosis is an iron-dependent regulated cell death marked by excessive oxidative phospholipids (PLs). The polyunsaturated fatty acids-containing phospholipids (PUFA-PLs) are highly susceptible to lipid peroxidation under oxidative stress. Numerous pulmonary diseases occurrences and degenerative pathologies are driven by ferroptosis. This review discusses the role of ferroptosis in the pathogenesis of pulmonary diseases including asthma, lung injury, lung cancer, fibrotic lung diseases, and pulmonary infection. Additionally, it is proposed that targeting ferroptosis is a potential treatment for pulmonary diseases, particularly drug-resistant lung cancer or antibiotic-resistant pulmonary infection, and reduces treatment-related adverse events.
Collapse
|
|
21
|
Fukumoto J, Lin M, Banday MM, Patil SS, Krishnamurthy S, Breitzig M, Soundararajan R, Galam L, Narala VR, Johns C, Patel K, Dunning J, Lockey RF, Sharma NS, Kolliputi N. Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis. Front Pharmacol 2022; 13:890380. [PMID: 35910393 PMCID: PMC9335372 DOI: 10.3389/fphar.2022.890380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/04/2022] [Indexed: 11/15/2022] Open
Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by mitochondrial dysfunction. However, details about the non-mitochondrial enzymes that sustain the proliferative nature of IPF are unclear. Aconitases are a family of enzymes that sustain metabolism inside and outside mitochondria. It is hypothesized that aconitase 1 (ACO1) plays an important role in the pathogenesis of IPF given that ACO1 represents an important metabolic hub in the cytoplasm. Objectives: To determine if ACO1 expression in IPF lungs shows specific patterns that may be important in the pathogenesis of IPF. To determine the similarities and differences in ACO1 expression in IPF, bleomycin-treated, and aging lungs. Methods: ACO1 expression in IPF lungs were characterized and compared to non-IPF controls by western blotting, immunostaining, and enzymatic activity assay. ACO1-expressing cell types were identified by multicolor immunostaining. Using similar methods, the expression profiles of ACO1 in IPF lungs versus bleomycin-treated and aged mice were investigated. Measurements and main results: Lower lobes of IPF lungs, unlike non-IPF controls, exhibit significantly high levels of ACO1. Most of the signals colocalize with von Willebrand factor (vWF), a lineage marker for vascular endothelial cells. Bleomycin-treated lungs also show high ACO1 expressions. However, most of the signals colocalize with E-cadherin and/or prosurfactant protein C, representative epithelial cell markers, in remodeled areas. Conclusions: A characteristic ACO1 expression profile observed in IPF vasculatures may be a promising diagnostic target. It also may give clues as to how de novo angiogenesis contributes to the irreversible nature of IPF.
Collapse
Affiliation(s)
- Jutaro Fukumoto
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Muling Lin
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Mudassir Meraj Banday
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Sahebgowda Sidramagowda Patil
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Sudarshan Krishnamurthy
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Mason Breitzig
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Ramani Soundararajan
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Lakshmi Galam
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Venkata Ramireddy Narala
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
- Department of Zoology, Yogi Vemana University, Kadapa, India
| | - Colleen Johns
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Kapilkumar Patel
- Pulmonary, Critical Care & Sleep Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Advanced Lung Diseases & Lung Transplantation, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - John Dunning
- Division of Cardiothoracic Surgery, Department of Surgery, University of South Florida, Tampa, FL, United States
| | - Richard F. Lockey
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
| | - Nirmal S. Sharma
- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- *Correspondence: Nirmal S. Sharma, ; Narasaiah Kolliputi,
| | - Narasaiah Kolliputi
- Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, United States
- Department of Molecular Medicine, University of South Florida, Tampa, FL, United States
- *Correspondence: Nirmal S. Sharma, ; Narasaiah Kolliputi,
| |
Collapse
|
|
22
|
Kumar A, Virender, Saini M, Mohan B, Shayoraj, Kamboj M. Colorimetric and Fluorescent Schiff Base Sensors for Trace Detection of Pollutants and Biologically Significant Cations: A Review (2010-2021). Microchem J 2022. [DOI: 10.1016/j.microc.2022.107798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
23
|
miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6520789. [PMID: 35720183 PMCID: PMC9203237 DOI: 10.1155/2022/6520789] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/03/2022] [Accepted: 05/20/2022] [Indexed: 12/28/2022]
Abstract
Hepatic ischemia-reperfusion injury (IRI) is an inevitable result of liver surgery. Steatotic livers are extremely sensitive to IRI and have worse tolerance. Ferroptosis is considered to be one of the main factors of organ IRI. This study is aimed at exploring the role of ferroptosis in the effect of heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) on steatotic liver IRI and its mechanism. An IRI model of a steatotic liver and a hypoxia reoxygenation (HR) model of steatotic hepatocytes (SHPs) were established. Rat BMMSCs were extracted and transfected with the Ho1 gene to establish HO-1/BMMSCs, and their exosomes were extracted by ultracentrifugation. Ireb2 was knocked down to verify its role in ferroptosis and cell injury in SHP-HR. Public database screening combined with quantitative real-time reverse transcription PCR identified microRNAs (miRNAs) targeting Ireb2 in HO-1/BMMSCs exosomes. miR-29a-3p mimic and inhibitor were used for functional verification experiments. Liver function, histopathology, terminal deoxynulceotidyl transferase nick-end-labeling staining, cell viability, mitochondrial membrane potential, and cell death were measured to evaluate liver tissue and hepatocyte injury. Ferroptosis was assessed by detecting the levels of IREB2, Fe2+, malondialdehyde, glutathione, lipid reactive oxygen species, glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2 mRNA, and mitochondrial morphology. The results revealed that HO-1/BMMSCs improved liver tissue and hepatocyte injury and suppressed ferroptosis in vivo and in vitro. The expression of IREB2 was increased in steatotic liver IRI and SHP-HR. Knocking down Ireb2 reduced the level of Fe2+ and inhibited ferroptosis. HO-1/BMMSC exosomes reduced the expression of IREB2 and inhibited ferroptosis and cell damage. Furthermore, we confirmed high levels of miR-29a-3p in HO-1/BMMSCs exosomes. Overexpression of miR-29a-3p downregulated the expression of Ireb2 and inhibited ferroptosis. Downregulation of miR-29a-3p blocked the protective effect of HO-1/BMMSC exosomes on SHP-HR cell injury. In conclusion, ferroptosis plays an important role in HO-1/BMMSC-mediated alleviation of steatotic liver IRI. HO-1/BMMSCs could suppress ferroptosis by targeting Ireb2 via the exosomal transfer of miR-29a-3p.
Collapse
|
|
24
|
Fan X, Barshop WD, Vashisht AA, Pandey V, Leal S, Rayatpisheh S, Jami-Alahmadi Y, Sha J, Wohlschlegel JA. Iron-regulated assembly of the cytosolic iron-sulfur cluster biogenesis machinery. J Biol Chem 2022; 298:102094. [PMID: 35654137 PMCID: PMC9243173 DOI: 10.1016/j.jbc.2022.102094] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/10/2022] [Accepted: 05/25/2022] [Indexed: 11/07/2022] Open
Abstract
The cytosolic iron–sulfur (Fe-S) cluster assembly (CIA) pathway delivers Fe-S clusters to nuclear and cytosolic Fe-S proteins involved in essential cellular functions. Although the delivery process is regulated by the availability of iron and oxygen, it remains unclear how CIA components orchestrate the cluster transfer under varying cellular environments. Here, we utilized a targeted proteomics assay for monitoring CIA factors and substrates to characterize the CIA machinery. We find that nucleotide-binding protein 1 (NUBP1/NBP35), cytosolic iron–sulfur assembly component 3 (CIAO3/NARFL), and CIA substrates associate with nucleotide-binding protein 2 (NUBP2/CFD1), a component of the CIA scaffold complex. NUBP2 also weakly associates with the CIA targeting complex (MMS19, CIAO1, and CIAO2B) indicating the possible existence of a higher order complex. Interactions between CIAO3 and the CIA scaffold complex are strengthened upon iron supplementation or low oxygen tension, while iron chelation and reactive oxygen species weaken CIAO3 interactions with CIA components. We further demonstrate that CIAO3 mutants defective in Fe-S cluster binding fail to integrate into the higher order complexes. However, these mutants exhibit stronger associations with CIA substrates under conditions in which the association with the CIA targeting complex is reduced suggesting that CIAO3 and CIA substrates may associate in complexes independently of the CIA targeting complex. Together, our data suggest that CIA components potentially form a metabolon whose assembly is regulated by environmental cues and requires Fe-S cluster incorporation in CIAO3. These findings provide additional evidence that the CIA pathway adapts to changes in cellular environment through complex reorganization.
Collapse
Affiliation(s)
- Xiaorui Fan
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA; Molecular Biology Institute, University of California, Los Angeles, California, USA
| | - William D Barshop
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Ajay A Vashisht
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Vijaya Pandey
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Stephanie Leal
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Shima Rayatpisheh
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Yasaman Jami-Alahmadi
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Jihui Sha
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
| |
Collapse
|
|
25
|
Gan J, Gu T, Hong L, Cai G. Ferroptosis-related genes involved in animal reproduction: An Overview. Theriogenology 2022; 184:92-99. [DOI: 10.1016/j.theriogenology.2022.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/20/2022] [Accepted: 02/25/2022] [Indexed: 11/30/2022]
|
|
26
|
The Relationship of Glutathione- S-Transferase and Multi-Drug Resistance-Related Protein 1 in Nitric Oxide (NO) Transport and Storage. Molecules 2021; 26:molecules26195784. [PMID: 34641326 PMCID: PMC8510172 DOI: 10.3390/molecules26195784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/21/2021] [Accepted: 09/21/2021] [Indexed: 12/18/2022] Open
Abstract
Nitric oxide is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, nitric oxide has been associated with many biological roles including cell signaling, macrophage cytotoxicity, and vasodilation. More recently, a model for nitric oxide trafficking has been proposed where nitric oxide is regulated in the form of dinitrosyl-dithiol-iron-complexes, which are much less toxic and have a significantly greater half-life than free nitric oxide. Our laboratory has previously examined this hypothesis in tumor cells and has demonstrated that dinitrosyl-dithiol-iron-complexes are transported and stored by multi-drug resistance-related protein 1 and glutathione-S-transferase P1. A crystal structure of a dinitrosyl-dithiol-iron complex with glutathione-S-transferase P1 has been solved that demonstrates that a tyrosine residue in glutathione-S-transferase P1 is responsible for binding dinitrosyl-dithiol-iron-complexes. Considering the roles of nitric oxide in vasodilation and many other processes, a physiological model of nitric oxide transport and storage would be valuable in understanding nitric oxide physiology and pathophysiology.
Collapse
|
|
27
|
Yao F, Cui X, Zhang Y, Bei Z, Wang H, Zhao D, Wang H, Yang Y. Iron regulatory protein 1 promotes ferroptosis by sustaining cellular iron homeostasis in melanoma. Oncol Lett 2021; 22:657. [PMID: 34386079 PMCID: PMC8299017 DOI: 10.3892/ol.2021.12918] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/17/2021] [Indexed: 12/26/2022] Open
Abstract
Melanoma, the most aggressive skin cancer, is mainly treated with BRAF inhibitors or immunotheareapy. However, most patients who initially responded to BRAF inhibitors or immunotheareapy become resistant following relapse. Ferroptosis is a form of regulated cell death characterized by its dependence on iron ions and the accumulation of lipid reactive oxygen species (ROS). Recent studies have demonstrated that ferroptosis is a good method for tumor treatment, and iron homeostasis is closely associated with ferroptosis. Iron regulatory protein (IRP)1 and 2 play important roles in maintaining iron homeostasis, but their functions in ferroptosis have not been investigated. The present study reported that the expression of IRP1 and IRP2 was increased by the ferroptosis inducers erastin and RSL3 in melanoma cells. Depletion of IRP1 significantly suppressed erastin- and RSL3-induced ferroptosis. IRP2 had a weak effect but could enhance the promoting function of IRP1 on ferroptosis. Further, erastin and RSL3 promoted the transition of aconitase 1 to IRP1, which regulated downstream iron metabolism proteins, including transferrin receptor (TFRC), ferroportin (FPN) and ferritin heavy chain 1 (FTH1). Moreover, overexpression of TFRC and knockdown of FPN and FTH1 significantly promoted erastin- and RSL3-induced ferroptosis in IRP1 knockdown melanoma cells. Collectively, the present findings indicate that IRP1 plays an essential role in erastin- and RSL3-induced ferroptosis by regulating iron homeostasis.
Collapse
Affiliation(s)
- Fengping Yao
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P.R. China
| | - Xiaohong Cui
- Psychiatry Department, Shanxi Bethune Hospital, Taiyuan, Shanxi 030000, P.R. China
| | - Ying Zhang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P.R. China
| | - Zhuchun Bei
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| | - Hongquan Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| | - Dongxu Zhao
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P.R. China
| | - Hong Wang
- State Key Laboratory of Pathogens and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, P.R. China
| | - Yongfei Yang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, P.R. China
| |
Collapse
|
|
28
|
Martí I Líndez AA, Reith W. Arginine-dependent immune responses. Cell Mol Life Sci 2021; 78:5303-5324. [PMID: 34037806 PMCID: PMC8257534 DOI: 10.1007/s00018-021-03828-4] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 03/23/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.
Collapse
Affiliation(s)
| | - Walter Reith
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| |
Collapse
|
|
29
|
Maio N, Zhang DL, Ghosh MC, Jain A, SantaMaria AM, Rouault TA. Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization. Semin Hematol 2021; 58:161-174. [PMID: 34389108 DOI: 10.1053/j.seminhematol.2021.06.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 12/11/2022]
Abstract
To maintain an adequate iron supply for hemoglobin synthesis and essential metabolic functions while counteracting iron toxicity, humans and other vertebrates have evolved effective mechanisms to conserve and finely regulate iron concentration, storage, and distribution to tissues. At the systemic level, the iron-regulatory hormone hepcidin is secreted by the liver in response to serum iron levels and inflammation. Hepcidin regulates the expression of the sole known mammalian iron exporter, ferroportin, to control dietary absorption, storage and tissue distribution of iron. At the cellular level, iron regulatory proteins 1 and 2 (IRP1 and IRP2) register cytosolic iron concentrations and post-transcriptionally regulate the expression of iron metabolism genes to optimize iron availability for essential cellular processes, including heme biosynthesis and iron-sulfur cluster biogenesis. Genetic malfunctions affecting the iron sensing mechanisms or the main pathways that utilize iron in the cell cause a broad range of human diseases, some of which are characterized by mitochondrial iron accumulation. This review will discuss the mechanisms of systemic and cellular iron sensing with a focus on the main iron utilization pathways in the cell, and on human conditions that arise from compromised function of the regulatory axes that control iron homeostasis.
Collapse
Affiliation(s)
- Nunziata Maio
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - De-Liang Zhang
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Manik C Ghosh
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Anshika Jain
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Anna M SantaMaria
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Tracey A Rouault
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
| |
Collapse
|
|
30
|
Terzi EM, Sviderskiy VO, Alvarez SW, Whiten GC, Possemato R. Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5. SCIENCE ADVANCES 2021; 7:7/22/eabg4302. [PMID: 34039609 PMCID: PMC8153722 DOI: 10.1126/sciadv.abg4302] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/08/2021] [Indexed: 05/23/2023]
Abstract
Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5-mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich's ataxia.
Collapse
Affiliation(s)
- Erdem M Terzi
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA
| | - Vladislav O Sviderskiy
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA
| | - Samantha W Alvarez
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA
| | - Gabrielle C Whiten
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA
| | - Richard Possemato
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA
| |
Collapse
|
|
31
|
Protchenko O, Baratz E, Jadhav S, Li F, Shakoury-Elizeh M, Gavrilova O, Ghosh MC, Cox JE, Maschek JA, Tyurin VA, Tyurina YY, Bayir H, Aron AT, Chang CJ, Kagan VE, Philpott CC. Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis. Hepatology 2021; 73:1176-1193. [PMID: 32438524 PMCID: PMC8364740 DOI: 10.1002/hep.31328] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 04/06/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell-death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. Although PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains open for study. The liver is highly specialized for iron uptake, utilization, storage, and secretion. APPROACH AND RESULTS Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell-autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative-stress response pathways, including the antiferroptotic mediator, glutathione peroxidase type 4. Although PCBP1-deleted livers were iron deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1-deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species (ROS), were hypersensitive to iron and pro-oxidants, and accumulated oxidatively damaged lipids because of the reactivity of unchaperoned iron. CONCLUSIONS Unchaperoned iron in PCBP1-deleted mouse hepatocytes leads to production of ROS, resulting in lipid peroxidation (LPO) and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the LPO that triggers the ferroptotic cell-death pathway.
Collapse
Affiliation(s)
| | - Ethan Baratz
- Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD
| | | | - Fengmin Li
- Genetics and Metabolism Section, NIDDK, NIH, Bethesda, MD
| | | | | | - Manik C. Ghosh
- Section on Human Iron Metabolism, NICHD, NIH, Bethesda, MD
| | - James E. Cox
- Deparment of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT
| | - J. Alan Maschek
- Deparment of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT
| | - Vladimir A. Tyurin
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA
| | - Yulia Y. Tyurina
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA
| | - Hülya Bayir
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA
| | - Allegra T. Aron
- Department of Chemistry, University of California, Berkeley, CA
| | | | - Valerian E. Kagan
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA
| | | |
Collapse
|
|
32
|
Shi F, Sun LX, Long S, Zhang Y. Pheochromocytoma as a cause of repeated acute myocardial infarctions, heart failure, and transient erythrocytosis: A case report and review of the literature. World J Clin Cases 2021; 9:951-959. [PMID: 33585644 PMCID: PMC7852630 DOI: 10.12998/wjcc.v9.i4.951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/25/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pheochromocytoma is a rare catecholamines-secreting tumor arising from chromaffin cells in the adrenal medulla. It classically presents with paroxysmal hypertension, headaches, palpitations, sweating, and metabolic disorders. Atypical presentations such as acute myocardial infarction, heart failure, cardiomyopathy, stroke, and transient erythrocytosis have been infrequently documented.
CASE SUMMARY We describe the case of a 72-year-old man diagnosed with pheochromocytoma presenting with non-ST segment elevation myocardial infarction, heart failure, and transient erythrocytosis with nonobstructed coronary arteries. This was his second heart attack. The patient was previously diagnosed with myocardial infarction, and an immense mass was found on the left adrenal gland 3 years prior. Based on clinical and laboratory findings, a diagnosis of pheochromocytoma was confirmed. His coronary angiogram showed nonobstructed coronary arteries except for a myocardial bridge in the left anterior descending branch. This was a form of type-2 myocardial infarction. The myocardial cell lesions were caused by sudden secretion of catecholamines by the pheochromocytoma. Even more atypically, his hemoglobin level was obviously elevated at admission, but after a few days of treatment with an alpha-adrenergic receptor blocker, it dropped to normal levels without additional treatment.
CONCLUSION Pheochromocytoma may be a cause of acute myocardial infarction, heart failure, and transient erythrocytosis.
Collapse
Affiliation(s)
- Fei Shi
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Li-Xian Sun
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Sen Long
- Department of Traditional Chinese Medicine, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Ying Zhang
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| |
Collapse
|
|
33
|
Urrutia PJ, Bórquez DA, Núñez MT. Inflaming the Brain with Iron. Antioxidants (Basel) 2021; 10:antiox10010061. [PMID: 33419006 PMCID: PMC7825317 DOI: 10.3390/antiox10010061] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 02/06/2023] Open
Abstract
Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood-brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.
Collapse
Affiliation(s)
- Pamela J. Urrutia
- Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile;
| | - Daniel A. Bórquez
- Center for Biomedical Research, Faculty of Medicine, Universidad Diego Portales, 8370007 Santiago, Chile;
| | - Marco Tulio Núñez
- Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024 Santiago, Chile;
- Correspondence: ; Tel.: +56-2-29787360
| |
Collapse
|
|
34
|
Mleczko‐Sanecka K, Silvestri L. Cell-type-specific insights into iron regulatory processes. Am J Hematol 2021; 96:110-127. [PMID: 32945012 DOI: 10.1002/ajh.26001] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/20/2020] [Accepted: 09/14/2020] [Indexed: 12/16/2022]
Abstract
Despite its essential role in many biological processes, iron is toxic when in excess due to its propensity to generate reactive oxygen species. To prevent diseases associated with iron deficiency or iron loading, iron homeostasis must be tightly controlled. Intracellular iron content is regulated by the Iron Regulatory Element-Iron Regulatory Protein (IRE-IRP) system, whereas systemic iron availability is adjusted to body iron needs chiefly by the hepcidin-ferroportin (FPN) axis. Here, we aimed to review advances in the field that shed light on cell-type-specific regulatory mechanisms that control or modify systemic and local iron balance, and how shifts in cellular iron levels may affect specialized cell functions.
Collapse
Affiliation(s)
| | - Laura Silvestri
- Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology IRCCS San Raffaele Scientific Institute Milan Italy
- Vita‐Salute San Raffaele University Milan Italy
| |
Collapse
|
|
35
|
Li Y, Jin C, Shen M, Wang Z, Tan S, Chen A, Wang S, Shao J, Zhang F, Zhang Z, Zheng S. Iron regulatory protein 2 is required for artemether -mediated anti-hepatic fibrosis through ferroptosis pathway. Free Radic Biol Med 2020; 160:845-859. [PMID: 32947011 DOI: 10.1016/j.freeradbiomed.2020.09.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/25/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Currently, the existing treatments have not cured the liver fibrosis thoroughly. Ferroptosis is a newly discovered way of cell death, which is closely related to many diseases. Previous studies have shown that ferroptosis plays an important role in the occurrence and development of liver fibrosis, but the further mechanism remains to be discovered. METHODS LX-2 cells were used as the research object, fibrosis activation index was detected by Western blot, PCR and Immunofluorescence, ferroptosis was detected by kits, the binding and interaction between IRP2 (iron regulatory protein 2) and STUB1 (STIP1 homology and U-box containing protein 1) were detected by Immunoprecipitation and ubiquitin test, and IRP2 knockdown mice were constructed by interfering plasmid to verify the results of in vitro experiment. RESULT Our research showed that ART (artemether) had a good anti-fibrosis effect in vivo and in vitro, and ferroptosis played an important role in this process. Further studies have found that ART could lead to the accumulation of IRP 2 a in hepatic stellate cell by inhibiting the ubiquitination of it, thus inducing the increase of iron in HSC (hepatic stellate cell), which could product a large number of ROS (reactive oxide species), resulting the occurrence of ferroptosis in cells. Our findings provided an experimental basis for ART to become a drug for the treatment of liver fibrosis. CONCLUSION Our results show that IRP2-Iron-ROS axis is necessary for ART to induce ferroptosis in HSC and play an anti-fibrotic effect.
Collapse
Affiliation(s)
- Yujia Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chun Jin
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Min Shen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhenyi Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shanzhong Tan
- Department of Integrated TCM and Western Medicine, Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, USA
| | - Shijun Wang
- Shandong Co-innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
| |
Collapse
|
|
36
|
Chiang S, Huang MLH, Park KC, Richardson DR. Antioxidant defense mechanisms and its dysfunctional regulation in the mitochondrial disease, Friedreich's ataxia. Free Radic Biol Med 2020; 159:177-188. [PMID: 32739593 DOI: 10.1016/j.freeradbiomed.2020.07.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
Abstract
Redox stress is associated with the pathogenesis of a wide variety of disease states. This can be amplified potentially through redox active iron deposits in oxidatively active organelles such as the mitochondrion. There are a number of disease states, including Friedreich's ataxia (FA) and sideroblastic anemia, where iron metabolism is dysregulated and leads to mitochondrial iron accumulation. Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.
Collapse
Affiliation(s)
- S Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - M L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - K C Park
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - D R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Centre for Cancer Cell Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia.
| |
Collapse
|
|
37
|
Iron homeostasis and oxidative stress: An intimate relationship. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:118535. [DOI: 10.1016/j.bbamcr.2019.118535] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/23/2019] [Accepted: 08/18/2019] [Indexed: 02/07/2023]
|
|
38
|
Relevance of the iron-responsive element (IRE) pseudotriloop structure for IRP1/2 binding and validation of IRE-like structures using the yeast three-hybrid system. Gene 2019; 710:399-405. [DOI: 10.1016/j.gene.2019.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/16/2019] [Accepted: 06/06/2019] [Indexed: 01/28/2023]
|
|
39
|
Boshuizen M, van Bruggen R, Zaat SA, Schultz MJ, Aguilera E, Motos A, Senussi T, Idone FA, Pelosi P, Torres A, Bassi GL, Juffermans NP. Development of a model for anemia of inflammation that is relevant to critical care. Intensive Care Med Exp 2019; 7:47. [PMID: 31346819 PMCID: PMC6658638 DOI: 10.1186/s40635-019-0261-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 05/30/2019] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND Anemia of inflammation (AI) is common in critically ill patients. Although this syndrome negatively impacts the outcome of critical illness, understanding of its pathophysiology is limited. Also, new therapies that increase iron availability for erythropoiesis during AI are upcoming. A model of AI induced by bacterial infections that are relevant for the critically ill is currently not available. This paper describes the development of an animal model for AI that is relevant for critical care research. RESULTS In experiments with rats, the rats were inoculated either repeatedly or with a slow release of Streptococcus pneumoniae or Pseudomonas aeruginosa. Rats became ill, but their hemoglobin levels remained stable. The use of a higher dose of bacteria resulted in a lethal model. Then, we turned to a model with longer disease duration, using pigs that were supported by mechanical ventilation after inoculation with P. aeruginosa. The pigs became septic 12 to 24 h after inoculation, with a statistically significant decrease in mean arterial pressure and base excess, while heart rate tended to increase. Pigs needed resuscitation and vasopressor therapy to maintain a mean arterial pressure > 60 mmHg. After 72 h, the pigs developed anemia (baseline 9.9 g/dl vs. 72 h, 7.6 g/dl, p = 0.01), characterized by statistically significant decreased iron levels, decreased transferrin saturation, and increased ferritin. Hepcidin levels tended to increase and transferrin levels tended to decrease. CONCLUSIONS Using pathogens commonly involved in pulmonary sepsis, AI could not be induced in rats. Conversely, in pigs, P. aeruginosa induced pulmonary sepsis with concomitant AI. This AI model can be applied to study the pathophysiology of AI in the critically ill and to investigate the effectivity and toxicity of new therapies that aim to increase iron availability.
Collapse
Affiliation(s)
- Margit Boshuizen
- Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands.
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, 1066, CX, The Netherlands.
| | - Robin van Bruggen
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, 1066, CX, The Netherlands
| | - Sebastian A Zaat
- Department of Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, 1105, AZ, The Netherlands
| | - Marcus J Schultz
- Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands
| | - Eli Aguilera
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
| | - Ana Motos
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
| | - Tarek Senussi
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
- Department of Surgical Sciences and Integrated Diagnostics (DISC), San Martino Policlinico Hospital - IRCCS for Oncology, 16132, Genova, Italy
| | - Francesco Antonio Idone
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
| | - Paolo Pelosi
- Department of Surgical Sciences and Integrated Diagnostics (DISC), San Martino Policlinico Hospital - IRCCS for Oncology, 16132, Genova, Italy
| | - Antonio Torres
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
| | - Gianluigi Li Bassi
- Department of Pulmonary and Critical Care Medicine, Thorax Institute, Hospital Clínic, 08036, Barcelona, Spain
| | - Nicole P Juffermans
- Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands
| |
Collapse
|
|
40
|
Ng SW, Norwitz SG, Norwitz ER. The Impact of Iron Overload and Ferroptosis on Reproductive Disorders in Humans: Implications for Preeclampsia. Int J Mol Sci 2019; 20:E3283. [PMID: 31277367 PMCID: PMC6651445 DOI: 10.3390/ijms20133283] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 07/01/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022] Open
Abstract
Iron is an essential element for the survival of most organisms, including humans. Demand for iron increases significantly during pregnancy to support growth and development of the fetus. Paradoxically, epidemiologic studies have shown that excessive iron intake and/or high iron status can be detrimental to pregnancy and is associated with reproductive disorders ranging from endometriosis to preeclampsia. Reproductive complications resulting from iron deficiency have been reviewed elsewhere. Here, we focus on reproductive disorders associated with iron overload and the contribution of ferroptosis-programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes-using preeclampsia as a model system. We propose that the clinical expressions of many reproductive disorders and pregnancy complications may be due to an underlying ferroptopathy (elemental iron-associated disease), characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis.
Collapse
Affiliation(s)
- Shu-Wing Ng
- Department of Obstetrics & Gynecology, Tufts University School of Medicine, Boston, MA 02111, USA.
- Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
| | | | - Errol R Norwitz
- Department of Obstetrics & Gynecology, Tufts University School of Medicine, Boston, MA 02111, USA.
- Mother Infant Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
| |
Collapse
|
|
41
|
Mayank AK, Pandey V, Vashisht AA, Barshop WD, Rayatpisheh S, Sharma T, Haque T, Powers DN, Wohlschlegel JA. An Oxygen-Dependent Interaction between FBXL5 and the CIA-Targeting Complex Regulates Iron Homeostasis. Mol Cell 2019; 75:382-393.e5. [PMID: 31229404 DOI: 10.1016/j.molcel.2019.05.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 04/03/2019] [Accepted: 05/10/2019] [Indexed: 01/06/2023]
Abstract
The iron-sensing protein FBXL5 is the substrate adaptor for a SKP1-CUL1-RBX1 E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins (IRPs). Here, we describe a mechanism of FBXL5 regulation involving its interaction with the cytosolic Fe-S cluster assembly (CIA) targeting complex composed of MMS19, FAM96B, and CIAO1. We demonstrate that the CIA-targeting complex promotes the ability of FBXL5 to degrade IRPs. In addition, the FBXL5-CIA-targeting complex interaction is regulated by oxygen (O2) tension displaying a robust association in 21% O2 that is severely diminished in 1% O2 and contributes to O2-dependent regulation of IRP degradation. Together, these data identify a novel oxygen-dependent signaling axis that links IRP-dependent iron homeostasis with the Fe-S cluster assembly machinery.
Collapse
Affiliation(s)
- Adarsh K Mayank
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Vijaya Pandey
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ajay A Vashisht
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - William D Barshop
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Shima Rayatpisheh
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Tanu Sharma
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Tisha Haque
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - David N Powers
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - James A Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
| |
Collapse
|
|
42
|
Zinc induces iron uptake and DMT1 expression in Caco-2 cells via a PI3K/IRP2 dependent mechanism. Biochem J 2019; 476:1573-1583. [DOI: 10.1042/bcj20180939] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/29/2019] [Accepted: 05/15/2019] [Indexed: 11/17/2022]
Abstract
Abstract
The absorption of iron is influenced by numerous dietary and physiological factors. We have previously demonstrated that zinc treatment of intestinal cells increases iron absorption via induction of the apical membrane iron transporter divalent metal ion transporter-1 (DMT1). To better understand the mechanisms of zinc-induced iron absorption, we have studied the effect of zinc on iron uptake, iron transporter and iron regulatory protein (IRP 1 and 2) expression and the impact of the PI3K pathway in differentiated Caco-2 cells, an intestinal cell culture model. We found that zinc induces DMT1 protein and mRNA expression. Zinc-induced DMT1 expression and iron absorption were inhibited by siRNA silencing of DMT1. Furthermore, zinc treatment led to increased abundance of IRP2 protein in cell lysates and in polysomal fractions, implying its binding to target mRNAs. Zinc treatment induced Akt phosphorylation, indicating the activation of the PI3K pathway. LY294002, a specific inhibitor of PI3K inhibited zinc-induced Akt phosphorylation, iron uptake, DMT1 and IRP2 expression. Furthermore, LY294002 also decreased the basal level of DMT1 mRNA but not protein expression. siRNA silencing of IRP2 led to down-regulation of both basal and zinc-induced DMT1 protein expression, implying possible involvement of post-transcriptional regulatory mechanisms. In agreement with these findings, zinc treatment stabilized DMT1 mRNA levels in actinomycin D-treated cells. Based on these findings, we conclude that zinc-induced iron absorption involves elevation of DMT1 expression by stabilization of its mRNA, by a PI3K/IRP2-dependent mechanism.
Collapse
|
|
43
|
Ast T, Meisel JD, Patra S, Wang H, Grange RMH, Kim SH, Calvo SE, Orefice LL, Nagashima F, Ichinose F, Zapol WM, Ruvkun G, Barondeau DP, Mootha VK. Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis. Cell 2019; 177:1507-1521.e16. [PMID: 31031004 PMCID: PMC6911770 DOI: 10.1016/j.cell.2019.03.045] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 02/11/2019] [Accepted: 03/22/2019] [Indexed: 12/16/2022]
Abstract
Friedreich's ataxia (FRDA) is a devastating, multisystemic disorder caused by recessive mutations in the mitochondrial protein frataxin (FXN). FXN participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.
Collapse
Affiliation(s)
- Tslil Ast
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Joshua D Meisel
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Shachin Patra
- Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
| | - Hong Wang
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Robert M H Grange
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Sharon H Kim
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Sarah E Calvo
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Lauren L Orefice
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Fumiaki Nagashima
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Fumito Ichinose
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Warren M Zapol
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Gary Ruvkun
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA
| | - David P Barondeau
- Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
| | - Vamsi K Mootha
- Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|
|
44
|
Rouault TA. The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways. Biometals 2019; 32:343-353. [PMID: 30923992 PMCID: PMC6584224 DOI: 10.1007/s10534-019-00191-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/18/2019] [Indexed: 02/07/2023]
Abstract
In recent years, iron sulfur (Fe–S) proteins have been identified as key players in mammalian metabolism, ranging from long-known roles in the respiratory complexes and the citric acid cycle, to more recently recognized roles in RNA and DNA metabolism. Fe–S cofactors have often been missed because of their intrinsic lability and oxygen sensitivity. More Fe–S proteins have now been identified owing to detection of their direct interactions with components of the Fe–S biogenesis machinery, and through use of informatics to detect a motif that binds the co-chaperone responsible for transferring nascent Fe–S clusters to domains of recipient proteins. Dissection of the molecular steps involved in Fe–S transfer to Fe–S proteins has revealed that direct and shielded transfer occurs through highly conserved pathways that operate in parallel in the mitochondrial matrix and in the cytosolic/nuclear compartments of eukaryotic cells. Because Fe–S clusters have the unusual ability to accept or donate single electrons in chemical reactions, their presence renders complex chemical reactions possible. In addition, Fe–S clusters may function as sensors that interconnect activity of metabolic pathways with cellular redox status. Presence in pathways that control growth and division may enable cells to regulate their growth according to sufficiency of energy stores represented by redox capacity, and oxidation of such proteins could diminish anabolic activities to give cells an opportunity to restore energy supplies. This review will discuss mechanisms of Fe–S biogenesis and delivery, and methods that will likely reveal important roles of Fe–S proteins in proteins not yet recognized as Fe–S proteins.
Collapse
|
|
45
|
Fujiwara T, Harigae H. Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia. Free Radic Biol Med 2019; 133:179-185. [PMID: 30098397 DOI: 10.1016/j.freeradbiomed.2018.08.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/02/2018] [Accepted: 08/04/2018] [Indexed: 01/19/2023]
Abstract
Sideroblastic anemia is a heterogeneous congenital and acquired disorder characterized by anemia and the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) is a rare disease caused by mutations in genes involved in the heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The most prevalent form of CSA is X-linked sideroblastic anemia, caused by mutations in the erythroid-specific δ-aminolevulinate synthase (ALAS2), which is the first enzyme of the heme biosynthesis pathway in erythroid cells. To date, a remarkable number of genetically undefined CSA cases remain, but a recent application of the next-generation sequencing technology has recognized novel causative genes for CSA. However, in most instances, the detailed molecular mechanisms of how defects of each gene result in the abnormal mitochondrial iron accumulation remain unclear. This review aims to cover the current understanding of the molecular pathophysiology of CSA.
Collapse
Affiliation(s)
- Tohru Fujiwara
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
| | - Hideo Harigae
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.
| |
Collapse
|
|
46
|
Abstract
Iron is an essential trace element in the human body, but excess iron is toxic as it contributes to oxidative damage. To keep iron concentration within the optimal physiologic range, iron metabolism at the cellular level and the whole systemic level are tightly regulated. Balance of iron homeostasis depends on the expression levels and activities of iron carriers, iron transporters, and iron regulatory and storage proteins. Divalent metal transporter 1 (DMT1) at the apical membrane of intestinal enterocyte brings in non-heme iron from the diet, whereas ferroportin 1 (FPN1) at the basal membrane exports iron into the circulation. Plasma transferrin (Tf) then carries iron to various tissues and cells. After binding to transferrin receptor 1 (TfR1), the complex is endocytosed into the cell, where iron enters the cytoplasm via DMT1 on the endosomal membrane. Free iron is either utilized in metabolic processes, such as synthesis of hemoglobin and Fe-S cluster, or sequestered in the cytosolic ferritin, serving as a cellular iron store. Excess iron can be exported from the cell via FPN1. The liver-derived peptide hepcidin plays a major regulatory role in controlling FPN1 level in the enterocyte, and thus controls the whole-body iron absorption. Inside the cells, iron regulatory proteins (IRPs) modulate the expressions of DMT1, TfR1, ferritin, and FPN1 via binding to the iron-responsive element (IRE) in their mRNAs. Both the release of hepcidin and the IRP-IRE interaction are coordinated with the fluctuation of the cellular iron level. Therefore, an adequate and steady iron supplement is warranted for the utilization of cells around the body. Investigations on the molecular mechanisms of cellular iron metabolism and regulation could advance the fields of iron physiology and pathophysiology.
Collapse
|
|
47
|
Zhou Y, Yang Y, Liu Y, Chang H, Liu K, Zhang X, Chang Y. Irp2 Knockout Causes Osteoporosis by Inhibition of Bone Remodeling. Calcif Tissue Int 2019; 104:70-78. [PMID: 30191282 DOI: 10.1007/s00223-018-0469-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 08/22/2018] [Indexed: 02/07/2023]
Abstract
It has been found that iron disorder may lead to osteoporosis. However, the mechanism has been little explored. In the present study, we try to investigate the effects of iron disorder on bone metabolism using Irp2 knockout (Irp2-/-) mice. Female Irp2-/- mice were used in this study. Bone mineral density (BMD) was measured by Micro-CT. Serum markers for bone turnover were measured by enzyme-linked immunosorbent assay. Content of iron was measured in bone and liver tissue, and Vitamin D 25-hydroxylase (CYP2R1) content was measured in liver tissue. Relative gene expression involved in iron export and uptake, and some genes involved in activities of osteoblast and osteoclast were all measured by real-time PCR and western blot. Compared to wild-type mice, Irp2-/- mice exhibited reduced BMD, bone iron deficiency, and hepatic iron overload. Serum levels of 25(OH)D3 and markers for bone formation such as bone alkaline phosphatase (Balp), bone-gla-protein (BGP), and type I collagen alpha1 chain (Col I α1) were decreased, while markers for bone resorption including cathepsin K (Ctsk) and tartrate-resistant acid phosphatase (Trap) were all significantly increased. Hepatic CYP2R1 level was decreased in Irp2-/- mice compared with wild-type control mice. Compared to wild-type C57BL6 control mice, the expression of genes involved in osteoblast activity such as Balp, BGP, and Col I α1 were all significantly decreased in bone tissue, while genes for osteoclast activity such as Ctsk and Trap were all markedly increased in Irp2-/- mice at mRNA level. Genes involved in iron storage, uptake, and exporting were also measured in bone tissue. Posttranscriptionally decreased ferritin (FTL), ferroportin 1 (FPN1), and increased transferrin receptor 1 (TfR1) gene expressions have been unexpectedly found in bone tissue of Irp2-/- mice. Irp2-/- mice exhibit reduced bone iron content and osteoporosis. Decreased circulating 25(OH)D3 levels promoted activity of osteoclast, while impaired activity of osteoblast may contribute to pathogenesis of osteoporosis. And, reduced bone iron content may not be totally caused by TfR1-dependent pathways.
Collapse
Affiliation(s)
- Yaru Zhou
- Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Yu Yang
- Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yan Liu
- Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hengrui Chang
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Kuanzhi Liu
- Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaojuan Zhang
- Department of Endocrinology, Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanzhong Chang
- College of Life Science, Hebei Normal University, Shijiazhuang, 050051, China.
| |
Collapse
|
|
48
|
Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M. Iron in the Tumor Microenvironment-Connecting the Dots. Front Oncol 2018; 8:549. [PMID: 30534534 PMCID: PMC6275298 DOI: 10.3389/fonc.2018.00549] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/06/2018] [Indexed: 12/18/2022] Open
Abstract
Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.
Collapse
Affiliation(s)
- Christa Pfeifhofer-Obermair
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Piotr Tymoszuk
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Verena Petzer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
49
|
Wang L, Liu X, You LH, Ci YZ, Chang S, Yu P, Gao G, Chang YZ. Hepcidin and iron regulatory proteins coordinately regulate ferroportin 1 expression in the brain of mice. J Cell Physiol 2018; 234:7600-7607. [PMID: 30370612 DOI: 10.1002/jcp.27522] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/10/2018] [Indexed: 12/31/2022]
Abstract
Iron plays an essential role in various cellular metabolic processes of the body. Maintenance of cellular iron homeostasis is particularly important for keeping the normal functions of the cells. Ferroportin 1 (FPN1) is the currently only known iron exporter on the cell membrane. It has been indicated that the regulation of FPN1 in response to the alteration of iron level mainly involves two processes, posttranscriptional repression by iron regulatory proteins (IRPs) and posttranslational degradation by hepcidin, the major iron-sensing hormone. However, whether there is any communication between the two types of regulations or which one plays dominant role has not been reported. In our study with IRP2-/- mice, we found that knockout of IRP2 increased FPN1 expression in the cerebral cortex of IRP2-/- mice, whereas the upregulation of FPN1 was more significant in IRP1/IRP2 dual knockdown fibroblasts. Interestingly, we found that the knockout of IRP2 severely affected the regulation effect of hepcidin on FPN1 in mouse brain. FPN1 level decreased dramatically in the brain of wild-type mice injected with hepcidin, but it did not decrease much in IRP2 knockout mice. Further investigation disclosed that the compromised hepcidin-FPN1 regulation in IRP2-/- cells was directly dependent on the existence of iron-responsive element (IRE) in FPN1 messenger RNA. These results indicate that IRPs and hepcidin coordinately regulate the FPN1 level in mice. This study will provide a more comprehensive understanding of the regulatory mechanisms of FPN1 expression.
Collapse
Affiliation(s)
- Lan Wang
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Xiaopeng Liu
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Lin-Hao You
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Yun-Zhe Ci
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Shiyang Chang
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Peng Yu
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Guofen Gao
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Yan-Zhong Chang
- Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| |
Collapse
|
|
50
|
Xu M, Tan X, Li N, Wu H, Wang Y, Xie J, Wang J. Differential regulation of estrogen in iron metabolism in astrocytes and neurons. J Cell Physiol 2018; 234:4232-4242. [PMID: 30132882 DOI: 10.1002/jcp.27188] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/17/2018] [Indexed: 12/19/2022]
Abstract
Previous studies have demonstrated an effect of estrogen on iron metabolism in peripheral tissues. The role of estrogen on brain iron metabolism is currently unknown. In this study, we investigated the effect and mechanism of estrogen on iron transport proteins. We demonstrated that the iron exporter ferroportin 1 (FPN1) and iron importer divalent metal transporter 1 (DMT1) were upregulated and iron content was decreased after estrogen treatment for 12 hr in primary cultured astrocytes. Hypoxia-inducible factor-1 alpha (HIF-1α) was upregulated, but HIF-2α remained unchanged after estrogen treatment for 12 hr in primary cultured astrocytes. In primary cultured neurons, DMT1 was downregulated, FPN1 was upregulated, iron content decreased, iron regulatory protein (IRP1) was downregulated, but HIF-1α and HIF-2α remained unchanged after estrogen treatment for 12 hr. These results suggest that the regulation of iron metabolism by estrogen in astrocytes and neurons is different. Estrogen increases FPN1 and DMT1 expression by inducing HIF-1α in astrocytes, whereas decreased expression of IRP1 may account for the decreased DMT1 and increased FPN1 expression in neurons.
Collapse
Affiliation(s)
- Manman Xu
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Xu Tan
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Na Li
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Hao Wu
- Clinical Medicine of Class Excellence, Grade 2013, Medical College of Qingdao University, Qingdao, China
| | - Yue Wang
- Clinical Medicine of Class 3, Grade 2014, Medical College of Qingdao University, Qingdao, China
| | - Junxia Xie
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| | - Jun Wang
- Department of Physiology and Pathophysiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China
| |
Collapse
|