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Chen J, Zhou Q, Su L, Ni L. Mitochondrial dysfunction: the hidden catalyst in chronic kidney disease progression. Ren Fail 2025; 47:2506812. [PMID: 40441691 PMCID: PMC12123951 DOI: 10.1080/0886022x.2025.2506812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Accepted: 05/10/2025] [Indexed: 06/02/2025] Open
Abstract
Chronic kidney disease (CKD) represents a global health epidemic, with approximately one-third of affected individuals ultimately necessitating renal replacement therapy or transplantation. The kidney, characterized by its exceptionally high energy demands, exhibits significant sensitivity to alterations in energy supply and mitochondrial function. In CKD, a compromised capacity for mitochondrial ATP synthesis has been documented. As research advances, the multifaceted roles of mitochondria, extending beyond their traditional functions in oxygen sensing and energy production, are increasingly acknowledged. Empirical studies have demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of fibrosis and cellular apoptosis in CKD. Targeting mitochondrial dysfunction holds substantial therapeutic promise, with emerging insights into its epigenetic regulation in CKD, particularly involving non-coding RNAs and DNA methylation. This article presents a comprehensive review of contemporary research on mitochondrial dysfunction in relation to the onset and progression of CKD. It elucidates the associated molecular mechanisms across various renal cell types and proposes novel research avenues for CKD treatment.
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Affiliation(s)
- Jinhu Chen
- Department of Nephrology, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuyuan Zhou
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Pathology, Liang Ping People’s Hospital of Chongqing, Chongqing, People’s Republic of China
| | - Lianjiu Su
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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2
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Perfetto M, Ishfaq M, Mohideen A, Rondelli CM, Gillis S, Tejero J, Stratman AN, Riggins R, Yien YY. FAM210B regulates iron homeostasis and sex-specific responses in stress erythropoiesis. Exp Hematol 2025:104797. [PMID: 40355042 DOI: 10.1016/j.exphem.2025.104797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 05/14/2025]
Abstract
Iron is required for redox homeostasis but poses toxicity risks due to its redox activity. Erythropoiesis hence requires tight regulation of iron utilization for hemoglobin synthesis. The requirement for iron in erythropoiesis has necessitated the evolution of mechanisms to handle the iron required for hemoglobinization. FAM210B was identified as a regulator of mitochondrial iron import and heme synthesis in erythroid cell culture and zebrafish models. Here, we demonstrate that although FAM210B is required for erythroid differentiation and heme synthesis under standard cell culture conditions, holotransferrin supplementation was sufficient to chemically complement the iron-deficient phenotype. To investigate the role of FAM210B in erythropoiesis, we used knockout mice. Although Fam210b-/- mice were viable and did not exhibit overt erythropoietic defects in the bone marrow, the male mice exhibited an increase in serum transferrin, suggesting sex-specific alterations in systemic iron sensing. On phlebotomy-induced stress erythropoiesis, Fam210b-/- mice exhibited differences in serum transferrin levels, and more starkly, had markedly smaller spleens, indicating defects in stress response. Fam210b-/- males had defects in neutrophil and monocyte numbers, as well as decreased erythroid progenitor numbers during erythropoietic stress. Together, our findings show that Fam210b plays a key role in the splenic response to erythropoietic stress. Our findings reveal a critical role for FAM210B in mediating splenic stress erythropoiesis and suggest it may act as a sex-specific regulator, potentially linked to androgen signaling.
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Affiliation(s)
- Mark Perfetto
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA; Department of Medicine, Division of Classical Hematology, University of Pittsburgh, Pittsburgh, PA
| | - Muhammad Ishfaq
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA; Department of Medicine, Division of Classical Hematology, University of Pittsburgh, Pittsburgh, PA
| | - Aiden Mohideen
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA; Department of Medicine, Division of Classical Hematology, University of Pittsburgh, Pittsburgh, PA
| | | | - Samantha Gillis
- Department of Biological Sciences, University of Delaware, Newark, DE
| | - Jesus Tejero
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Amber N Stratman
- Department of Cell Biology and Physiology, Washington University in St Louis School of Medicine, St Louis, M
| | - Rebecca Riggins
- Georgetown Lombardi Comprehensive Cancer Center, Washington, DC
| | - Yvette Y Yien
- Pittsburgh Heart Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA; Department of Medicine, Division of Classical Hematology, University of Pittsburgh, Pittsburgh, PA.
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Wang H, Liu Q, Cheng S, Li L, Shen W, Ge W. Single-Cell Transcriptomic Analysis of the Potential Mechanisms of Follicular Development in Stra8-Deficient Mice. Int J Mol Sci 2025; 26:3734. [PMID: 40332359 PMCID: PMC12027774 DOI: 10.3390/ijms26083734] [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: 02/18/2025] [Revised: 04/05/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
Follicle development is a critical process in mammalian reproduction, with significant implications for ovarian reserve and fertility. Stra8 is a known key factor regulating the initiation of meiosis; however, oocyte-like cells still appear in Stra8-deficient mice. Nevertheless, the underlying mechanism remains unclear and requires further investigation. Therefore, we used single-cell RNA sequencing to construct a comprehensive transcriptional atlas of ovarian cells from both wild-type and Stra8-deficient mice at embryonic stages E14.5 and E16.5. With stringent quality control, we obtained a total of 14,755 single cells of six major cell types. A further fine-scale analysis of the germ cell clusters revealed notable heterogeneity between wild-type and Stra8-deficient mice. Compared to the wild-type mice, the deficiency in Stra8 led to the downregulation of meiosis-related genes (e.g., Pigp, Tex12, and Sycp3), and the upregulation of apoptosis-related genes (e.g., Fos, Jun, and Actb), thereby hindering the meiotic process. Notably, we observed that, following Stra8 deficiency, the expression levels of Sub1 and Stk31 remained elevated at this stage. Furthermore, an RNA interference analysis confirmed the potential role of these genes as regulatory factors in the formation of primordial follicle-like cells. Additionally, Stra8 deficiency disrupted the signaling between germ cells and pregranulosa cells that is mediated by Mdk-Sdc1, leading to the abnormal expression of the PI3K/AKT signaling pathway. Together, these results shed light on the molecular processes governing germ cell differentiation and folliculogenesis, emphasizing the complex role of Stra8 in ovarian function.
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Affiliation(s)
| | | | | | | | - Wei Shen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China; (H.W.); (Q.L.); (S.C.); (L.L.)
| | - Wei Ge
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao 266109, China; (H.W.); (Q.L.); (S.C.); (L.L.)
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Zhang C, Yang X, Xue Y, Li H, Zeng C, Chen M. The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis. J Clin Transl Hepatol 2025; 13:233-252. [PMID: 40078199 PMCID: PMC11894391 DOI: 10.14218/jcth.2024.00348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/19/2024] [Accepted: 12/31/2024] [Indexed: 03/14/2025] Open
Abstract
Solute carrier (SLC) family transporters are crucial transmembrane proteins responsible for transporting various molecules, including amino acids, electrolytes, fatty acids, and nucleotides. To date, more than fifty SLC transporter subfamilies have been identified, many of which are linked to the progression of hepatic steatosis and fibrosis. These conditions are often caused by factors such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which are major contributors to the global liver disease burden. The activity of SLC members regulates the transport of substrates across biological membranes, playing key roles in lipid synthesis and metabolism, mitochondrial function, and ferroptosis. These processes, in turn, influence the function of hepatocytes, hepatic stellate cells, and macrophages, thereby contributing to the development of hepatic steatosis and fibrosis. Additionally, some SLC transporters are involved in drug transport, acting as critical regulators of drug-induced hepatic steatosis. Beyond substrate transport, certain SLC members also exhibit additional functions. Given the pivotal role of the SLC family in hepatic steatosis and fibrosis, this review aimed to summarize the molecular mechanisms through which SLC transporters influence these conditions.
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Affiliation(s)
| | | | - Yi Xue
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Huan Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chuanfei Zeng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Tanwar SS, Dwivedi S, Khan S, Sharma S. Cardiomyopathies and a brief insight into DOX-induced cardiomyopathy. Egypt Heart J 2025; 77:29. [PMID: 40064787 PMCID: PMC11893974 DOI: 10.1186/s43044-025-00628-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/23/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Cardiomyopathy is a heterogeneous group of myocardial disorders characterized by structural and functional abnormalities of the heart muscle. It is classified into primary (genetic, mixed, or acquired) and secondary categories, resulting in various phenotypes including dilated, hypertrophic, and restrictive patterns. Hypertrophic cardiomyopathy, the most common primary form, can cause exertional dyspnea, presyncope, and sudden cardiac death. Dilated cardiomyopathy typically presents with heart failure symptoms, while restrictive cardiomyopathy is rarer and often associated with systemic diseases. Diagnosis involves a comprehensive evaluation including history, physical examination, electrocardiography, and echocardiography. Treatment options range from pharmacotherapy and lifestyle modifications to implantable cardioverter-defibrillators and heart transplantation in refractory cases. MAIN BODY Anthracyclines, particularly doxorubicin, have emerged as crucial components in cancer treatment, demonstrating significant antitumor activity across various malignancies. These drugs have become standard in numerous chemotherapy regimens, improving patient outcomes. However, their use is associated with severe cardiotoxicity, including cardiomyopathy and heart failure. The mechanisms of anthracycline action and toxicity are complex, involving DNA damage, iron-mediated free radical production, and disruption of cardiovascular homeostasis. Doxorubicin-induced cardiomyopathy (DIC) is a severe complication of cancer treatment with a poor prognosis and limited effective treatments. The pathophysiology of DIC involves multiple mechanisms, including oxidative stress, inflammation, mitochondrial damage, and calcium homeostasis disorder. Despite extensive research, no effective treatment for established DIC is currently available. Dexrazoxane is the only FDA-approved protective agent, but it has limitations. Recent studies have explored various potential therapeutic approaches, including natural drugs, endogenous substances, new dosage forms, and herbal medicines. However, the lack of experimental models incorporating pre-existing cancer limits the understanding of DIC pathophysiology and treatment efficacy. CONCLUSION Cardiomyopathy, whether primary or secondary, poses a significant clinical challenge due to its varying etiologies and poor prognosis in advanced stages. Anthracycline-induced cardiomyopathy is a severe complication of chemotherapy, with doxorubicin being a notable contributor. Despite advancements in cancer therapies, the cardiotoxic effects of anthracyclines necessitate further investigation into effective preventive strategies and therapeutic interventions to improve patient outcomes.
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Affiliation(s)
| | - Sumeet Dwivedi
- Acropolis Institute of Pharmaceutical Education and Research, Indore, India
| | - Sheema Khan
- The University of Texas Rio Grande Valley, Edinburg, US
| | - Seema Sharma
- Shri Vaishnav Vidyapeeth Vishwadvidyalaya, Indore, India.
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Liu FF, Li K. Molecular characterization underlying IFN-α2 treatment in polycythemia vera: a transcriptomic overview. Mol Cell Biochem 2025:10.1007/s11010-025-05238-7. [PMID: 40029555 DOI: 10.1007/s11010-025-05238-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
Polycythemia vera (PV) is the most common chronic myeloproliferative neoplasm (MPN) in adults. Pegylated interferon-α2 (IFN-α2) is an effective and safe drug for the treatment of PV. However, the mechanisms of its action in PV are still not fully understood. Using the WGCNA and Limma algorithm, we found a subset of IFN-α2 sensitive genes and four gene co-expression modules. Meanwhile, we also found 820 genes were differentially expressed in PV compared with healthy controls. By integrating the above results, several differentially expressed genes (DEGs) that were up- or down-regulated in PV but showed opposite alterations in the IFN-α2-treated group were found. These genes were mainly related to three types of biological processes (metal ion homeostasis, metabolic/catabolic process, and Jak-STAT signaling pathway), the dysfunctions of which were prevalent in PV. Moreover, we applied another threshold-free analysis method to compare global gene expression between IFN-α2 treated PV, PV, and control groups. Results showed the transcriptome changes of PV versus controls were negatively correlated with that of IFN-α2 treated versus untreated PV, indicating IFN-α2 treatment could partially reverse the dysregulated gene expression profile due to PV pathology. In summary, interferon may alleviate the progression of PV through multiple pathways. The findings may be of assistance in understanding the molecular basis underlying this treatment.
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Affiliation(s)
- Fang-Fang Liu
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, People's Republic of China
| | - Ke Li
- Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Hankou District, Wuhan, 430030, Hubei, People's Republic of China.
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7
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Liu C, Liu Z, Dong Z, Liu S, Kan H, Zhang S. Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis. J Genet Genomics 2025:S1673-8527(25)00024-4. [PMID: 39862922 DOI: 10.1016/j.jgg.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 01/17/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025]
Abstract
Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO. We summarize how various types of fatty acids (FAs), including saturated, monounsaturated, and polyunsaturated FAs, differentially influence ferroptosis when incorporated into phospholipids. Furthermore, we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis, shedding light on therapeutic avenues for ferroptosis-associated diseases.
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Affiliation(s)
- Conghe Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Zhihao Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Zheng Dong
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Sijin Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haidong Kan
- School of Public Health, Key Lab of Public Health Safety of the Ministry of Education and NHC Key Lab of Health Technology Assessment, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China
| | - Shuping Zhang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
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8
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Zhu L, Du Y. A promising new approach to cancer therapy: Manipulate ferroptosis by hijacking endogenous iron. Int J Pharm 2024; 662:124517. [PMID: 39084581 DOI: 10.1016/j.ijpharm.2024.124517] [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: 04/08/2024] [Revised: 07/12/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
Ferroptosis, a form of regulated cell death characterized by iron-dependent phospholipid peroxidation, has emerged as a focal point in the field of cancer therapy. Compared with other cell death modes such as apoptosis and necrosis, ferroptosis exhibits many distinct characteristics in the molecular mechanisms and cell morphology, offering a promising avenue for combating cancers that are resistant to conventional therapeutic modalities. In light of the serious side effects associated with current Fenton-modulating ferroptosis therapies utilizing exogenous iron-based inorganic nanomaterials, hijacking endogenous iron could serve as an effective alternative strategy to trigger ferroptosis through targeting cellular iron regulatory mechanisms. A better understanding of the underlying iron regulatory mechanism in the process of ferroptosis has shed light on the current findings of endogenous ferroptosis-based nanomedicine strategies for cancer therapy. Here in this review article, we provide a comprehensive discussion on the regulatory network of iron metabolism and its pivotal role in ferroptosis, and present recent updates on the application of nanoparticles endowed with the ability to hijack endogenous iron for ferroptosis. We envision that the insights in the study may expedite the development and translation of endogenous ferroptosis-based nanomedicines for effective cancer treatment.
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Affiliation(s)
- Luwen Zhu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yongzhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China.
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9
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Polesel M, Wildschut MHE, Doucerain C, Kuhn M, Flace A, Sá Zanetti L, Steck AL, Wilhelm M, Ingles-Prieto A, Wiedmer T, Superti-Furga G, Manolova V, Dürrenberger F. Image-based quantification of mitochondrial iron uptake via Mitoferrin-2. Mitochondrion 2024; 78:101889. [PMID: 38692382 DOI: 10.1016/j.mito.2024.101889] [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: 10/26/2023] [Revised: 04/26/2024] [Accepted: 04/28/2024] [Indexed: 05/03/2024]
Abstract
Iron is a trace element that is critical for most living organisms and plays a key role in a wide variety of metabolic processes. In the mitochondrion, iron is involved in producing iron-sulfur clusters and synthesis of heme and kept within physiological ranges by concerted activity of multiple molecules. Mitochondrial iron uptake is mediated by the solute carrier transporters Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28). While Mitoferrin-1 is mainly involved in erythropoiesis, the cellular function of the ubiquitously expressed Mitoferrin-2 remains less well defined. Furthermore, Mitoferrin-2 is associated with several human diseases, including cancer, cardiovascular and metabolic diseases, hence representing a potential therapeutic target. Here, we developed a robust approach to quantify mitochondrial iron uptake mediated by Mitoferrin-2 in living cells. We utilize HEK293 cells with inducible expression of Mitoferrin-2 and measure iron-induced quenching of rhodamine B[(1,10-phenanthroline-5-yl)-aminocarbonyl]benzyl ester (RPA) fluorescence and validate this assay for medium-throughput screening. This assay may allow identification and characterization of Mitoferrin-2 modulators and could enable drug discovery for this target.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Alvaro Ingles-Prieto
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Tabea Wiedmer
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Giulio Superti-Furga
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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10
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Hu Y, Li J, Hu L, Liu F, Chen R, Xu L, Tang Z, Lu B, Yu J. BACH1 impairs hepatocyte regeneration after hepatectomy with repeated ischemia/reperfusion by reprogramming energy metabolism and exacerbating oxidative stress. Biochem Pharmacol 2024; 226:116377. [PMID: 38906228 DOI: 10.1016/j.bcp.2024.116377] [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: 03/09/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 06/23/2024]
Abstract
BTB and CNC homology 1 (BACH1) regulates biological processes, including energy metabolism and oxidative stress. Insufficient liver regeneration after hepatectomy remains an issue for surgeons. The Pringle maneuver is widely used during hepatectomy and induces ischemia/reperfusion (I/R) injury in hepatocytes. A rat model of two-thirds partial hepatectomy with repeated I/R treatment was used to simulate clinical hepatectomy with Pringle maneuver. Delayed recovery of liver function after hepatectomy with the repeated Pringle maneuver in clinic and impaired liver regeneration in rat model were observed. Highly elevated lactate levels, along with reduced mitochondrial complex III and IV activities in liver tissues, indicated that the glycolytic phenotype was promoted after hepatectomy with repeated I/R. mRNA expression profile analysis of glycolysis-related genes in clinical samples and further verification experiments in rat models showed that high BACH1 expression levels correlated with the glycolytic phenotype after hepatectomy with repeated I/R. BACH1 overexpression restricted the proliferative potential of hepatocytes stimulated with HGF. High PDK1 expression and high lactate levels, together with low mitochondrial complex III and IV activities and reduced ATP concentrations, were detected in BACH1-overexpressing hepatocytes with HGF stimulation. Moreover, HO-1 expression was downregulated, and oxidative stress was exacerbated in the BACH1-overexpressing hepatocytes with HGF stimulation. Cell experiments involving repeated hypoxia/reoxygenation revealed that reactive oxygen species accumulation triggered the TGF-β1/BACH1 axis in hepatocytes. Finally, inhibiting BACH1 with the inhibitor hemin effectively restored the liver regenerative ability after hepatectomy with repeated I/R. These results provide a potential therapeutic strategy for impaired liver regeneration after repeated I/R injury.
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Affiliation(s)
- Yanxin Hu
- School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China; Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Jiandong Li
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Liangfeng Hu
- Department of Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Fang Liu
- Department of Pathology, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Ruanchang Chen
- School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China; Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Luohang Xu
- School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China; Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Zekai Tang
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China
| | - Baochun Lu
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
| | - Jianhua Yu
- Department of Hepato-Biliary-Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
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11
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Chai Z, Zheng J, Shen J. Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke. CNS Neurosci Ther 2024; 30:e14865. [PMID: 39042604 PMCID: PMC11265528 DOI: 10.1111/cns.14865] [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: 04/11/2024] [Revised: 06/27/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
Ferroptosis is a newly discovered form of programmed cell death that is non-caspase-dependent and is characterized by the production of lethal levels of iron-dependent lipid reactive oxygen species (ROS). In recent years, ferroptosis has attracted great interest in the field of cerebral infarction because it differs morphologically, physiologically, and genetically from other forms of cell death such as necrosis, apoptosis, autophagy, and pyroptosis. In addition, ROS is considered to be an important prognostic factor for ischemic stroke, making it a promising target for stroke treatment. This paper summarizes the induction and defense mechanisms associated with ferroptosis, and explores potential treatment strategies for ischemic stroke in order to lay the groundwork for the development of new neuroprotective drugs.
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Affiliation(s)
- Zhaohui Chai
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
| | - Jiesheng Zheng
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
| | - Jian Shen
- Department of NeurosurgeryFirst Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhou CityChina
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12
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Krieg S, Rohde T, Rausch T, Butthof L, Wendler-Link L, Eckert C, Breuhahn K, Galy B, Korbel J, Billmann M, Breinig M, Tschaharganeh DF. Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers. Genome Med 2024; 16:83. [PMID: 38886830 PMCID: PMC11181659 DOI: 10.1186/s13073-024-01357-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/07/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions. METHODS We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities. RESULTS We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential. CONCLUSIONS Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.
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Affiliation(s)
- Stephan Krieg
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Rohde
- Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
| | - Tobias Rausch
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | - Luise Butthof
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lena Wendler-Link
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christoph Eckert
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Bruno Galy
- Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jan Korbel
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
| | - Maximilian Billmann
- Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
| | - Marco Breinig
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
| | - Darjus F Tschaharganeh
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
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13
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Klag KA, Bell R, Jia X, Seguin A, Maschek JA, Bronner M, Cox JE, Round JL, Ward DM. Low-Iron Diet-Induced Fatty Liver Development Is Microbiota Dependent and Exacerbated by Loss of the Mitochondrial Iron Importer Mitoferrin2. Nutrients 2024; 16:1804. [PMID: 38931165 PMCID: PMC11206261 DOI: 10.3390/nu16121804] [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: 05/01/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Iron deficiency is the number one nutritional problem worldwide. Iron uptake is regulated at the intestine and is highly influenced by the gut microbiome. Blood from the intestines drains directly into the liver, informing iron status and gut microbiota status. Changes in either iron or the microbiome are tightly correlated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD). To investigate the underlying mechanisms of the development of MASLD that connect altered iron metabolism and gut microbiota, we compared specific pathogen free (SPF) or germ-free (GF) mice, fed a normal or low-iron diet. SPF mice on a low-iron diet showed reduced serum triglycerides and MASLD. In contrast, GF low-iron diet-fed mice showed increased serum triglycerides and did not develop hepatic steatosis. SPF mice showed significant changes in liver lipid metabolism and increased insulin resistance that was dependent upon the presence of the gut microbiota. We report that total body loss of mitochondrial iron importer Mitoferrin2 (Mfrn2-/-) exacerbated the development of MASLD on a low-iron diet with significant lipid metabolism alterations. Our study demonstrates a clear contribution of the gut microbiome, dietary iron, and Mfrn2 in the development of MASLD and metabolic syndrome.
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Affiliation(s)
- Kendra A. Klag
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
| | - Rickesha Bell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
| | - Xuan Jia
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
| | - Alexandra Seguin
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
| | - J. Alan Maschek
- Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA; (J.A.M.); (J.E.C.)
| | - Mary Bronner
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
- Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
| | - James E. Cox
- Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT 84112, USA; (J.A.M.); (J.E.C.)
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| | - June L. Round
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
| | - Diane M. Ward
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (K.A.K.); (R.B.); (X.J.); (A.S.); (M.B.); (J.L.R.)
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14
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Xie T, Yao L, Li X. Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases. Antioxidants (Basel) 2024; 13:659. [PMID: 38929098 PMCID: PMC11200795 DOI: 10.3390/antiox13060659] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.
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Affiliation(s)
- Tiancheng Xie
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Li Yao
- Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, China;
| | - Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
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15
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Guan H, Xiao L, Hao K, Zhang Q, Wu D, Geng Z, Duan B, Dai H, Xu R, Feng X. SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL. J Diabetes Res 2024; 2024:5511454. [PMID: 38736904 PMCID: PMC11088465 DOI: 10.1155/2024/5511454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 03/21/2024] [Accepted: 03/26/2024] [Indexed: 05/14/2024] Open
Abstract
Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.
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Affiliation(s)
- Hua Guan
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Lin Xiao
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Kaikai Hao
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Qiang Zhang
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Dongliang Wu
- Department of Cardiology, Xianyang Hospital of Yan'an University, Xianyang 712000, China
| | - Zhanyi Geng
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Bowen Duan
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, Shaanxi, China
| | - Hui Dai
- Department of Clinical Medicine, Gansu Medical College, Pingliang 744000, China
| | - Ruifen Xu
- Department of Anesthesiology, Shaanxi Provincial Peoples Hospital, Xi'an 710068, China
| | - Xuyang Feng
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
- Department of Neurology, Xianyang Hospital of Yan'an University, Xianyang 712000, China
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16
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Kumar A, Ye C, Nkansah A, Decoville T, Fogo GM, Sajjakulnukit P, Reynolds MB, Zhang L, Quaye O, Seo YA, Sanderson TH, Lyssiotis CA, Chang CH. Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism. Proc Natl Acad Sci U S A 2024; 121:e2318420121. [PMID: 38621136 PMCID: PMC11047099 DOI: 10.1073/pnas.2318420121] [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: 10/29/2023] [Accepted: 03/14/2024] [Indexed: 04/17/2024] Open
Abstract
In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.
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Affiliation(s)
- Ajay Kumar
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Chenxian Ye
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Afia Nkansah
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
- Department of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, AccraG4522, Ghana
| | - Thomas Decoville
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Garrett M. Fogo
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI48109
| | - Peter Sajjakulnukit
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI48109
| | - Mack B. Reynolds
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Li Zhang
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI48109
| | - Osbourne Quaye
- Department of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, AccraG4522, Ghana
| | - Young-Ah Seo
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI48109
| | - Thomas H. Sanderson
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI48109
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Costas A. Lyssiotis
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI48109
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI48109
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI48109
| | - Cheong-Hee Chang
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI48109
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17
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Shao M, Cheng H, Li X, Qiu Y, Zhang Y, Chang Y, Fu J, Shen M, Xu X, Feng D, Han Y, Yue S, Zhou Y, Luo Z. Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis. Theranostics 2024; 14:2687-2705. [PMID: 38773980 PMCID: PMC11103499 DOI: 10.7150/thno.94072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/08/2024] [Indexed: 05/24/2024] Open
Abstract
Rationale: Pulmonary fibrosis is a chronic progressive lung disease with limited therapeutic options. We previously revealed that there is iron deposition in alveolar epithelial type II cell (AECII) in pulmonary fibrosis, which can be prevented by the iron chelator deferoxamine. However, iron in the cytoplasm and the mitochondria has two relatively independent roles and regulatory systems. In this study, we aimed to investigate the role of mitochondrial iron deposition in AECII injury and pulmonary fibrosis, and to find potential therapeutic strategies. Methods: BLM-treated mice, MLE-12 cells, and primary AECII were employed to establish the mouse pulmonary fibrosis model and epithelial cells injury model, respectively. Mitochondrial transplantation, siRNA and plasmid transfection, western blotting (WB), quantitative real-time polymerase chain reaction (RT-qPCR), polymerase chain reaction (PCR), immunofluorescence, immunoprecipitation (IP), MitoSOX staining, JC-1 staining, oxygen consumption rate (OCR) measurement, and Cell Counting Kit-8 (CCK8) assay were utilized to elucidate the role of mitochondrial iron deposition in cell and lung fibrosis and determine its mechanism. Results: This study showed that prominent mitochondrial iron deposition occurs within AECII in bleomycin (BLM)-induced pulmonary fibrosis mouse model and in BLM-treated MLE-12 epithelial cells. Further, the study revealed that healthy mitochondria rescue BLM-damaged AECII mitochondrial iron deposition and cell damage loss. Mitoferrin-2 (MFRN2) is the main transporter that regulates mitochondrial iron metabolism by transferring cytosolic iron into mitochondria, which is upregulated in BLM-treated MLE-12 epithelial cells. Direct overexpression of MFRN2 causes mitochondrial iron deposition and cell damage. In this study, decreased ubiquitination of the ubiquitin ligase F-box/LRR-repeat protein 5 (FBXL5) degraded iron-reactive element-binding protein 2 (IREB2) and promoted MFRN2 expression as well as mitochondrial iron deposition in damaged AECII. Activation of the prostaglandin E2 receptor EP4 subtype (EP4) receptor signaling pathway counteracted mitochondrial iron deposition by downregulating IREB2-MFRN2 signaling through upregulation of FBXL5. This intervention not only reduced mitochondrial iron content but also preserved mitochondrial function and protected against AECII damage after BLM treatment. Conclusion: Our findings highlight the unexplored roles, mechanisms, and regulatory approaches of abnormal mitochondrial iron metabolism of AECII in pulmonary fibrosis. Therefore, this study deepens the understanding of the mechanisms underlying pulmonary fibrosis and offers a promising strategy for developing effective therapeutic interventions using the EP4 receptor activator.
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Affiliation(s)
- Min Shao
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Haipeng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China
| | - Xiaohong Li
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China
| | - Yujia Qiu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yunna Zhang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yanfen Chang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Jiafeng Fu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Mengxia Shen
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Xinxin Xu
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Dandan Feng
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Yang Han
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - ShaoJie Yue
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Yan Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Ziqiang Luo
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China
- Hunan Key Laboratory of Organ Fibrosis, Changsha, Hunan, 410013, China
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18
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Han R, Liu L, Wang Y, Wu R, Yang Y, Zhao Y, Jian L, Yuan Y, Zhang L, Gu Y, Gao C, Ye J. Microglial SLC25A28 Deficiency Ameliorates the Brain Injury After Intracerebral Hemorrhage in Mice by Restricting Aerobic Glycolysis. Inflammation 2024; 47:591-608. [PMID: 38085466 DOI: 10.1007/s10753-023-01931-1] [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: 09/10/2023] [Revised: 10/20/2023] [Accepted: 11/06/2023] [Indexed: 05/07/2024]
Abstract
The microglia overactivation-induced neuroinflammation is a significant cause of the brain injury after intracerebral hemorrhage (ICH). Iron homeostasis is crucial for microglia activation, but the mechanism and causality still need further study. This study aimed to explore the roles and mechanism of the mitochondrial iron transporter SLC25A28 in microglia activation after ICH. Intrastriatal injection of autologous blood was used to establish ICH model, and the neuroinflammation, iron metabolism and brain injuries were assessed in wildtype or microglia-specific SLC25A28 knockout mice after ICH. Mitochondria iron levels and microglial function were determined in SLC25A28 overexpressed or deleted microglia. The extracellular acidification rate (ECAR), lactate production, and glycolytic enzyme levels were used to determine aerobic glycolysis. The results showed that ICH stimulated mitochondrial iron overload, and synchronously upregulated the SLC25A28 expression. In vitro, SLC25A28 overexpression increased mitochondrial iron levels in microglia. Interestingly, microglial SLC25A28 deficiency ameliorated neuroinflammation, brain edema, blood-brain barrier injury and ethological alterations in mice after ICH. Mechanically, SLC25A28 deficiency inhibited microglial activation by restricting the aerobic glycolysis. Moreover, zinc protoporphyrin could reduce SLC25A28 expression and mitigated brain injury. SLC25A28 plays crucial roles in mitochondrial iron homeostasis and microglia activation after ICH, and it might be a potential therapeutic target for ICH.
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Affiliation(s)
- Ruili Han
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
- Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, 710038, Xi'an, Shaanxi, China
| | - Lei Liu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Yuying Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Ruolin Wu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Ying Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Yuanlin Zhao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Lele Jian
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Yuan Yuan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China
| | - Lijun Zhang
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, 710038, Xi'an, Shaanxi, China
| | - Yu Gu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China.
| | - Changjun Gao
- Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, 710038, Xi'an, Shaanxi, China.
| | - Jing Ye
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China.
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19
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Cox SN, Lo Giudice C, Lavecchia A, Poeta ML, Chiara M, Picardi E, Pesole G. Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue. Biomolecules 2024; 14:411. [PMID: 38672428 PMCID: PMC11048214 DOI: 10.3390/biom14040411] [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: 02/01/2024] [Revised: 03/19/2024] [Accepted: 03/23/2024] [Indexed: 04/28/2024] Open
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.
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Affiliation(s)
- Sharon Natasha Cox
- Department of Biosciences, Biotechnology and Environment, University of Bari “Aldo Moro”, 70126 Bari, Italy; (A.L.); (M.L.P.); (E.P.)
| | - Claudio Lo Giudice
- Institute of Biomedical Technologies, National Research Council, 70126 Bari, Italy;
| | - Anna Lavecchia
- Department of Biosciences, Biotechnology and Environment, University of Bari “Aldo Moro”, 70126 Bari, Italy; (A.L.); (M.L.P.); (E.P.)
| | - Maria Luana Poeta
- Department of Biosciences, Biotechnology and Environment, University of Bari “Aldo Moro”, 70126 Bari, Italy; (A.L.); (M.L.P.); (E.P.)
| | - Matteo Chiara
- Department of Biosciences, University of Milan, 20133 Milan, Italy;
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, National Research Council, 70126 Bari, Italy
| | - Ernesto Picardi
- Department of Biosciences, Biotechnology and Environment, University of Bari “Aldo Moro”, 70126 Bari, Italy; (A.L.); (M.L.P.); (E.P.)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, National Research Council, 70126 Bari, Italy
| | - Graziano Pesole
- Department of Biosciences, Biotechnology and Environment, University of Bari “Aldo Moro”, 70126 Bari, Italy; (A.L.); (M.L.P.); (E.P.)
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, National Research Council, 70126 Bari, Italy
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20
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Mi D, Yanatori I, Zheng H, Kong Y, Hirayama T, Toyokuni S. Association of poly( rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Free Radic Res 2024; 58:261-275. [PMID: 38599240 DOI: 10.1080/10715762.2024.2340711] [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: 11/02/2023] [Accepted: 03/15/2024] [Indexed: 04/12/2024]
Abstract
Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.
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Affiliation(s)
- Danyang Mi
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Izumi Yanatori
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hao Zheng
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yingyi Kong
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tasuku Hirayama
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan
| | - Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan
- Center for Integrated Sciences of Low-temperature Plasma Core Research (iPlasma Core), Tokai National Higher Education and Research System, Nagoya, Japan
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21
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Galy B, Conrad M, Muckenthaler M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol 2024; 25:133-155. [PMID: 37783783 DOI: 10.1038/s41580-023-00648-1] [Citation(s) in RCA: 249] [Impact Index Per Article: 249.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2023] [Indexed: 10/04/2023]
Abstract
In mammals, hundreds of proteins use iron in a multitude of cellular functions, including vital processes such as mitochondrial respiration, gene regulation and DNA synthesis or repair. Highly orchestrated regulatory systems control cellular and systemic iron fluxes ensuring sufficient iron delivery to target proteins is maintained, while limiting its potentially deleterious effects in iron-mediated oxidative cell damage and ferroptosis. In this Review, we discuss how cells acquire, traffick and export iron and how stored iron is mobilized for iron-sulfur cluster and haem biogenesis. Furthermore, we describe how these cellular processes are fine-tuned by the combination of various sensory and regulatory systems, such as the iron-regulatory protein (IRP)-iron-responsive element (IRE) network, the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy pathway, the prolyl hydroxylase domain (PHD)-hypoxia-inducible factor (HIF) axis or the nuclear factor erythroid 2-related factor 2 (NRF2) regulatory hub. We further describe how these pathways interact with systemic iron homeostasis control through the hepcidin-ferroportin axis to ensure appropriate iron fluxes. This knowledge is key for the identification of novel therapeutic opportunities to prevent diseases of cellular and/or systemic iron mismanagement.
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Affiliation(s)
- Bruno Galy
- German Cancer Research Center (DKFZ), Division of Virus-associated Carcinogenesis (F170), Heidelberg, Germany
| | - Marcus Conrad
- Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Martina Muckenthaler
- Department of Paediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany.
- Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
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22
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He Z, He W, Hu C, Liao J, Deng W, Sun H, Huang Q, Chen W, Zhang L, Liu M, Dong J. Cross-species comparison illuminates the importance of iron homeostasis for splenic anti-immunosenescence. Aging Cell 2023; 22:e13982. [PMID: 37681451 PMCID: PMC10652311 DOI: 10.1111/acel.13982] [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: 02/20/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution. A close relationship between B:T cell ratio and immunosenescence was detected, as B:T cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of ROS-induced damage in mouse. PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.
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Affiliation(s)
- Ziqing He
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
- Faculty of Health SciencesUniversity of MacauMacauChina
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Weiya He
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
- Faculty of Health SciencesUniversity of MacauMacauChina
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Chuanxia Hu
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Jiayu Liao
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Wenjun Deng
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Haijian Sun
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
- Faculty of Health SciencesUniversity of MacauMacauChina
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Qingpei Huang
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Weilue Chen
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Libiao Zhang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and UtilizationInstitute of Zoology, Guangdong Academy of SciencesGuangzhouChina
| | - Meiling Liu
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
| | - Ji Dong
- GMU‐GIBH Joint School of Life Sciences, The Guangdong‐Hong Kong‐Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National LaboratoryGuangzhou Medical UniversityGuangzhouChina
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
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23
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Perfetto M, Rondelli CM, Gillis S, Stratman AN, Yien YY. FAM210B is dispensable for erythroid differentiation in adult mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.26.559581. [PMID: 37823037 PMCID: PMC10563458 DOI: 10.1101/2023.09.26.559581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Iron plays a central role in cellular redox processes, but its ability to adopt multiple oxidation states also enables it to catalyze deleterious reactions. The requirement for iron in erythropoiesis has necessitated the evolution of mechanisms with which to handle the iron required for hemoglobinization. FAM210B was identified as a regulator of mitochondrial iron import and heme synthesis in erythroid cell culture and zebrafish models. In this manuscript, we demonstrate that while FAM210B is required for erythroid differentiation and heme synthesis under standard cell culture conditions, holotransferrin supplementation was sufficient to chemically complement the iron-deficient phenotype. As the biology of FAM210B is complex and context specific, and whole-organism studies on FAM210 proteins have been limited, we sought to unravel the role of FAM210B in erythropoiesis using knockout mice. We were surprised to discover that Fam210b -/- mice were viable and the adults did not have erythropoietic defects in the bone marrow. In contrast to studies in C. elegans, Fam210b -/- mice were also fertile. There were some modest phenotypes, such as a slight increase in lymphocytes and white cell count in Fam210b -/- females, as well as an increase in body weight in Fam210b -/- males. However, our findings suggest that FAM210B may play a more important role in cellular iron homeostasis under iron deficient conditions. Here, we will discuss the cell culture conditions used in iron metabolism studies that can account for the disparate finding on FAM210B function. Moving forward, resolving these discrepancies will be important in identifying novel iron homeostasis genes.
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24
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Kadam A, Jadiya P, Tomar D. Post-translational modifications and protein quality control of mitochondrial channels and transporters. Front Cell Dev Biol 2023; 11:1196466. [PMID: 37601094 PMCID: PMC10434574 DOI: 10.3389/fcell.2023.1196466] [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: 03/29/2023] [Accepted: 07/24/2023] [Indexed: 08/22/2023] Open
Abstract
Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
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Affiliation(s)
- Ashlesha Kadam
- Department of Internal Medicine, Section of Cardiovascular Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Pooja Jadiya
- Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Dhanendra Tomar
- Department of Internal Medicine, Section of Cardiovascular Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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25
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Pasquadibisceglie A, Bonaccorsi di Patti MC, Musci G, Polticelli F. Membrane Transporters Involved in Iron Trafficking: Physiological and Pathological Aspects. Biomolecules 2023; 13:1172. [PMID: 37627237 PMCID: PMC10452680 DOI: 10.3390/biom13081172] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Iron is an essential transition metal for its involvement in several crucial biological functions, the most notable being oxygen storage and transport. Due to its high reactivity and potential toxicity, intracellular and extracellular iron levels must be tightly regulated. This is achieved through transport systems that mediate cellular uptake and efflux both at the level of the plasma membrane and on the membranes of lysosomes, endosomes and mitochondria. Among these transport systems, the key players are ferroportin, the only known transporter mediating iron efflux from cells; DMT1, ZIP8 and ZIP14, which on the contrary, mediate iron influx into the cytoplasm, acting on the plasma membrane and on the membranes of lysosomes and endosomes; and mitoferrin, involved in iron transport into the mitochondria for heme synthesis and Fe-S cluster assembly. The focus of this review is to provide an updated view of the physiological role of these membrane proteins and of the pathologies that arise from defects of these transport systems.
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Affiliation(s)
| | | | - Giovanni Musci
- Department of Biosciences and Territory, University of Molise, 86090 Pesche, Italy;
| | - Fabio Polticelli
- Department of Sciences, University Roma Tre, 00146 Rome, Italy;
- National Institute of Nuclear Physics, Roma Tre Section, 00146 Rome, Italy
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26
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Ali MY, Griguer CE, Flor S, Oliva CR. Mitoferrin-1 Promotes Proliferation and Abrogates Protein Oxidation via the Glutathione Pathway in Glioblastoma. Antioxidants (Basel) 2023; 12:antiox12020349. [PMID: 36829908 PMCID: PMC9952016 DOI: 10.3390/antiox12020349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
Median overall survival is very low in patients with glioblastoma (GBM), largely because these tumors become resistant to therapy. Recently, we found that a decrease in the cytosolic labile iron pool underlies the acquisition of radioresistance. Both cytosolic and mitochondrial iron are important for regulating ROS production, which largely facilitates tumor progression and response to therapy. Here, we investigated the role of the mitochondrial iron transporters mitoferrin-1 (MFRN1) and mitoferrin-2 (MFRN2) in GBM progression. Analysis of The Cancer Genome Atlas database revealed upregulation of MFRN1 mRNA and downregulation of MFRN2 mRNA in GBM tumor tissue compared with non-GBM tissue, yet only the tumor expression level of MFRN1 mRNA negatively correlated with overall survival in patients. Overexpression of MFRN1 in glioma cells significantly increased the level of mitochondrial iron, enhanced the proliferation rate and anchorage-independent growth of these cells, and significantly decreased mouse survival in an orthotopic model of glioma. Finally, MFRN1 overexpression stimulated the upregulation of glutathione, which protected glioma cells from 4-hydroxynonenal-induced protein damage. Overall, these results demonstrate a mechanistic link between MFRN1-mediated mitochondrial iron metabolism and GBM progression. Manipulation of MFRN1 may provide a new therapeutic strategy for improving clinical outcomes in patients with GBM.
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Affiliation(s)
- Md Yousuf Ali
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
| | - Corinne E. Griguer
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA
| | - Susanne Flor
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
- Free Radical & Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA
| | - Claudia R. Oliva
- Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA
- Correspondence:
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27
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Su Y, Liu Z, Xie K, Ren Y, Li C, Chen W. Ferroptosis: A Novel Type of Cell Death in Male Reproduction. Genes (Basel) 2022; 14:genes14010043. [PMID: 36672785 PMCID: PMC9858973 DOI: 10.3390/genes14010043] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/14/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Ferroptosis, an iron-dependent type of regulated cell death, is triggered by the accumulation of lethal lipid peroxides. Due to its potential in exploring disease progression and highly targeted therapies, it is still a widely discussed topic nowadays. In recent studies, it was found that ferroptosis was induced when testicular tissue was exposed to some high-risk factors, such as cadmium (Cd), busulfan, and smoking accompanied by a variety of reproductive damage characteristics, including changes in the specific morphology and ferroptosis-related features. In this literature-based review, we summarize the related mechanisms of ferroptosis and elaborate upon its relationship network in the male reproductive system in terms of three significant events: the abnormal iron metabolism, dysregulation of the Cyst(e)ine/GSH/GPX4 axis, and lipid peroxidation. It is meaningful to deeply explore the relationship between ferroptosis and the male reproductive system, which may provide suggestions regarding pristine therapeutic targets and novel drugs.
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Affiliation(s)
- Yanjing Su
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
| | - Zelan Liu
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
| | - Keyu Xie
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
| | - Yingxin Ren
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
| | - Chunyun Li
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
- Department of Clinical Medicine, Hunan Normal University School of Medicine, Changsha 410013, China
- Correspondence: (C.L.); (W.C.)
| | - Wei Chen
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, China
- Department of Nursing, Hunan Normal University School of Medicine, Changsha 410013, China
- Correspondence: (C.L.); (W.C.)
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28
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Mitoferrin, Cellular and Mitochondrial Iron Homeostasis. Cells 2022; 11:cells11213464. [PMID: 36359860 PMCID: PMC9658796 DOI: 10.3390/cells11213464] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/28/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
Iron is essential for many cellular processes, but cellular iron homeostasis must be maintained to ensure the balance of cellular signaling processes and prevent disease. Iron transport in and out of the cell and cellular organelles is crucial in this regard. The transport of iron into the mitochondria is particularly important, as heme and the majority of iron-sulfur clusters are synthesized in this organelle. Iron is also required for the production of mitochondrial complexes that contain these iron-sulfur clusters and heme. As the principal iron importers in the mitochondria of human cells, the mitoferrins have emerged as critical regulators of cytosolic and mitochondrial iron homeostasis. Here, we review the discovery and structure of the mitoferrins, as well as the significance of these proteins in maintaining cytosolic and mitochondrial iron homeostasis for the prevention of cancer and many other diseases.
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29
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Ma C, Han L, Zhu Z, Heng Pang C, Pan G. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem Pharmacol 2022; 205:115242. [PMID: 36084708 DOI: 10.1016/j.bcp.2022.115242] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide. Minerals including iron, copper, zinc, and selenium, fulfil an essential role in various biochemical processes. Moreover, the identification of ferroptosis and cuproptosis further underscores the importance of intracellular mineral homeostasis. However, perturbation of minerals has been frequently reported in patients with NAFLD and related diseases. Interestingly, studies have attempted to establish an association between mineral disorders and NAFLD pathological features, including oxidative stress, mitochondrial dysfunction, inflammatory response, and fibrogenesis. In this review, we aim to provide an overview of the current understanding of mineral metabolism (i.e., absorption, utilization, and transport) and mineral interactions in the pathogenesis of NAFLD. More importantly, this review highlights potential therapeutic strategies, challenges, future directions for targeting mineral metabolism in the treatment of NAFLD.
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Affiliation(s)
- Chenhui Ma
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Han
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zheying Zhu
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
| | - Cheng Heng Pang
- Department of Chemical and Environmental Engineering, University of Nottingham Ningbo China, Ningbo 315100, China.
| | - Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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30
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Yien YY, Perfetto M. Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins. Front Cell Dev Biol 2022; 10:895521. [PMID: 35832791 PMCID: PMC9272004 DOI: 10.3389/fcell.2022.895521] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/12/2022] [Indexed: 11/19/2022] Open
Abstract
Heme plays a central role in diverse, life-essential processes that range from ubiquitous, housekeeping pathways such as respiration, to highly cell-specific ones such as oxygen transport by hemoglobin. The regulation of heme synthesis and its utilization is highly regulated and cell-specific. In this review, we have attempted to describe how the heme synthesis machinery is regulated by mitochondrial homeostasis as a means of coupling heme synthesis to its utilization and to the metabolic requirements of the cell. We have focused on discussing the regulation of mitochondrial heme synthesis enzymes by housekeeping proteins, transport of heme intermediates, and regulation of heme synthesis by macromolecular complex formation and mitochondrial metabolism. Recently discovered mechanisms are discussed in the context of the model organisms in which they were identified, while more established work is discussed in light of technological advancements.
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31
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Medlock AE, Hixon JC, Bhuiyan T, Cobine PA. Prime Real Estate: Metals, Cofactors and MICOS. Front Cell Dev Biol 2022; 10:892325. [PMID: 35669513 PMCID: PMC9163361 DOI: 10.3389/fcell.2022.892325] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/02/2022] [Indexed: 12/23/2022] Open
Abstract
Metals are key elements for the survival and normal development of humans but can also be toxic to cells when mishandled. In fact, even mild disruption of metal homeostasis causes a wide array of disorders. Many of the metals essential to normal physiology are required in mitochondria for enzymatic activities and for the formation of essential cofactors. Copper is required as a cofactor in the terminal electron transport chain complex cytochrome c oxidase, iron is required for the for the formation of iron-sulfur (Fe-S) clusters and heme, manganese is required for the prevention of oxidative stress production, and these are only a few examples of the critical roles that mitochondrial metals play. Even though the targets of these metals are known, we are still identifying transporters, investigating the roles of known transporters, and defining regulators of the transport process. Mitochondria are dynamic organelles whose content, structure and localization within the cell vary in different tissues and organisms. Our knowledge of the impact that alterations in mitochondrial physiology have on metal content and utilization in these organelles is very limited. The rates of fission and fusion, the ultrastructure of the organelle, and rates of mitophagy can all affect metal homeostasis and cofactor assembly. This review will focus of the emerging areas of overlap between metal homeostasis, cofactor assembly and the mitochondrial contact site and cristae organizing system (MICOS) that mediates multiple aspects of mitochondrial physiology. Importantly the MICOS complexes may allow for localization and organization of complexes not only involved in cristae formation and contact between the inner and outer mitochondrial membranes but also acts as hub for metal-related proteins to work in concert in cofactor assembly and homeostasis.
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Affiliation(s)
- Amy E. Medlock
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States
- Augusta University/University of Georgia Medical Partnership, University of Georgia, Athens, GA, United States
| | - J. Catrice Hixon
- Department of Biological Sciences, Auburn University, Auburn, AL, United States
| | - Tawhid Bhuiyan
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States
| | - Paul A. Cobine
- Department of Biological Sciences, Auburn University, Auburn, AL, United States
- *Correspondence: Paul A. Cobine,
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Jia R, Hou Y, Feng W, Li B, Zhu J. Alterations at biochemical, proteomic and transcriptomic levels in liver of tilapia (Oreochromis niloticus) under chronic exposure to environmentally relevant level of glyphosate. CHEMOSPHERE 2022; 294:133818. [PMID: 35114268 DOI: 10.1016/j.chemosphere.2022.133818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/03/2022] [Accepted: 01/28/2022] [Indexed: 06/14/2023]
Abstract
The toxicity of glyphosate (Gly) on aquatic animals has received attention from many researchers. However, the chronic toxicity mechanism of Gly on fish has not yet been clarified entirely. Thus, this study aimed to explore the potential toxicity mechanism of Gly at 2 mg/L, a possibly existing concentration in the aquatic environment, via biochemical, transcriptomic and proteomic analyses in the liver of tilapia. Long-term Gly exposure increased lipid content, and altered redox status in liver. Transcriptomic analysis revealed that Gly exposure changed dramatically the expression of 225 genes in liver, including 94 up-regulated genes and 131 down-regulated genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses showed that these genes were predominantly enriched in ion transport, lipid metabolism and PPAR (peroxisome proliferator-activated receptor) signaling pathway. Meanwhile, at proteomic level, long-term Gly exposure resulted in alteration of 21 proteins, which were principally related to hepatic metabolism function. In conclusion, our data displayed a potential toxicity, mainly manifested as redox imbalance and dysregulation of metabolism function, in the liver of tilapia after long-term Gly exposure at 2 mg/L. This study provided novel insight into underlying toxicity mechanism of long-term Gly exposure at an environmentally relevant concentration in fish.
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Affiliation(s)
- Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Yiran Hou
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Wenrong Feng
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Bing Li
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Jian Zhu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
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Liu S, Cao X, Wang D, Zhu H. Iron metabolism: State of the art in hypoxic cancer cell biology. Arch Biochem Biophys 2022; 723:109199. [DOI: 10.1016/j.abb.2022.109199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/08/2023]
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Cheng R, Dhorajia VV, Kim J, Kim Y. Mitochondrial iron metabolism and neurodegenerative diseases. Neurotoxicology 2022; 88:88-101. [PMID: 34748789 PMCID: PMC8748425 DOI: 10.1016/j.neuro.2021.11.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 01/03/2023]
Abstract
Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.
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Affiliation(s)
- Ruiying Cheng
- Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, USA
| | | | - Jonghan Kim
- Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, USA.
| | - Yuho Kim
- Department of Physical Therapy and Kinesiology, University of Massachusetts Lowell, USA.
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Gaitskell-Phillips G, Martín-Cano FE, Ortiz-Rodríguez JM, Silva-Rodríguez A, da Silva-Álvarez E, Gil MC, Ortega-Ferrusola C, Peña FJ. The seminal plasma proteins Peptidyl arginine deaminase 2, rRNA adenine N (6)-methyltransferase and KIAA0825 are linked to better motility post thaw in stallions. Theriogenology 2022; 177:94-102. [PMID: 34687941 DOI: 10.1016/j.theriogenology.2021.10.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 10/04/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023]
Abstract
Seminal plasma plays an important role in sperm physiology. Seminal plasma proteins vehiculated in microvesicles, carry RNAs and proteins with a potential role in early embryo development. Additionally, proteins present in seminal plasma participate in redox regulation and energy metabolism. In view of these facts, we hypothesized that differences in protein composition of the seminal plasma among stallions may help to explain differences in freeze-ability seen among them. Three independent ejaculates from 10 different stallions of varying breeds were frozen using standard protocols in our laboratory. Aliquots of the ejaculate were separated and stored at -80 °C until further proteomic analysis. Semen analysis was performed using computer assisted sperm analysis and flow cytometry. Significant differences in proteome composition of seminal plasma were observed in the group of stallions showing better motility post thaw. 3116 proteins were identified, and of these, 34 were differentially expressed in stallions with better motility post thaw, 4 of them were also differentially expressed in stallions with different percentages of linearly motile sperm post thaw and 1 protein, Midasin, was expressed in stallions showing high circular velocity post thaw. Seminal plasma proteins may play a major role in sperm functionality; being vehiculated through extracellular vesicles and participating in sperm physiology. Bioinformatic analysis identifies discriminant proteins able to predict the outcome of cryopreservation, identifying potential new biomarkers to assess ejaculate quality.
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Affiliation(s)
- Gemma Gaitskell-Phillips
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Francisco E Martín-Cano
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - José M Ortiz-Rodríguez
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Antonio Silva-Rodríguez
- Facility of Innovation and Analysis in Animal Source Foodstuffs, University of Extremadura, Cáceres, Spain
| | - Eva da Silva-Álvarez
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Maria C Gil
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Cristina Ortega-Ferrusola
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - Fernando J Peña
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain.
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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Wang X, An P, Gu Z, Luo Y, Luo J. Mitochondrial Metal Ion Transport in Cell Metabolism and Disease. Int J Mol Sci 2021; 22:7525. [PMID: 34299144 PMCID: PMC8305404 DOI: 10.3390/ijms22147525] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 12/19/2022] Open
Abstract
Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases.
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Affiliation(s)
- Xuan Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (X.W.); (P.A.)
| | - Peng An
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (X.W.); (P.A.)
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA;
| | - Yongting Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (X.W.); (P.A.)
| | - Junjie Luo
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (X.W.); (P.A.)
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38
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Kondo S, Ferdousi F, Yamauchi K, Suidasari S, Yokozawa M, Harrabi MM, Tominaga KI, Isoda H. Comprehensive transcriptome analysis of erythroid differentiation potential of olive leaf in haematopoietic stem cells. J Cell Mol Med 2021; 25:7229-7243. [PMID: 34180123 PMCID: PMC8335692 DOI: 10.1111/jcmm.16752] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/15/2021] [Accepted: 06/08/2021] [Indexed: 12/13/2022] Open
Abstract
Anaemia is one of the leading causes of disability in young adults and is associated with increased morbidity and mortality in elderly. With a global target to reduce the disease burden of anaemia, recent researches focus on novel compounds with the ability to induce erythropoiesis and regulate iron homeostasis. We aimed to explore the biological events and potential polypharmacological effects of water-extracted olive leaf (WOL) on human bone marrow-derived haematopoietic stem cells (hHSCs) using a comprehensive gene expression analysis. HPLC analysis identifies six bioactive polyphenols in the WOL. Treatment with WOL for 12 days regulated gene expressions related to erythroid differentiation, oxygen homeostasis, iron homeostasis, haem metabolism and Hb biosynthesis in hHSCs. Functional clustering analysis reveals several major functions of WOL such as ribosomal biogenesis and mitochondrial translation machinery, glycolytic process, ATP biosynthesis and immune response. Additionally, the colonies of both primitive and mature erythroid progenitors, CFU-E and BFU-E, were significantly increased in WOL-treated hHSCs. The expressions of erythroid markers, CD47, glycophorin A (GYPA), and transferrin receptor (TFRC) and adult Hb subunits-HBA and HBB were also confirmed in immunofluorescent staining and flow cytometer analysis in WOL-treated hHSCs. It is well known that induction of lineage-specific differentiation, as well as the maturation of early haematopoietic precursors into fully mature erythrocytes, involves multiple simultaneous biological events and complex signalling networks. In this regard, our genome-wide transcriptome profiling with microarray study on WOL-treated hHSCs provides general insights into the multitarget prophylactic and/or therapeutic potential of WOL in anaemia and other haematological disorders.
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Affiliation(s)
- Shinji Kondo
- R&D Center for Tailor-Made QOL, University of Tsukuba, Tsukuba, Japan
| | - Farhana Ferdousi
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.,AIST-University of Tsukuba Open innovation laboratory for food and medicinal resource engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan.,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
| | | | | | | | - Mohamed Moncef Harrabi
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan
| | - Ken-Ichi Tominaga
- AIST-University of Tsukuba Open innovation laboratory for food and medicinal resource engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan
| | - Hiroko Isoda
- R&D Center for Tailor-Made QOL, University of Tsukuba, Tsukuba, Japan.,Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.,AIST-University of Tsukuba Open innovation laboratory for food and medicinal resource engineering (FoodMed-OIL), University of Tsukuba, Tsukuba, Japan.,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
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Koleini N, Shapiro JS, Geier J, Ardehali H. Ironing out mechanisms of iron homeostasis and disorders of iron deficiency. J Clin Invest 2021; 131:e148671. [PMID: 34060484 DOI: 10.1172/jci148671] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients' symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.
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40
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Wang D, Ye P, Kong C, Chao Y, Yu W, Jiang X, Luo J, Gu Y, Chen SL. Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis. Exp Cell Res 2021; 402:112552. [PMID: 33711329 DOI: 10.1016/j.yexcr.2021.112552] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/27/2021] [Accepted: 03/02/2021] [Indexed: 01/12/2023]
Abstract
Endothelial dysfunction is an early step in the development of atherosclerotic cardiovascular disease. Iron overload can lead to excessive mitochondrial reactive oxygen species (mtROS) production, resulting in mitochondrial dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an iron transporter in the inner mitochondrial membrane. This study aimed to assess whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis progression and to explore the potential mechanism. We observed significant upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein E-/- (ApoE-/-) mice and in TNF-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE-/- mice markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in aortas and reduced monocyte infiltration into the vascular wall. Furthermore, TNF-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε overexpression increased Mfrn2 stability by inhibiting its ubiquitination. Together, our results reveal that Mfrn2 deficiency attenuates endothelial dysfunction by decreasing iron levels within the mitochondria and mitochondrial dysfunction. These findings may provide new insights into preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.
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Affiliation(s)
- Dongchen Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Peng Ye
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Chaohua Kong
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yuelin Chao
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wande Yu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaomin Jiang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jie Luo
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yue Gu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Shao-Liang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Singh LP, Yumnamcha T, Devi TS. Mitophagy, Ferritinophagy and Ferroptosis in Retinal Pigment Epithelial Cells Under High Glucose Conditions: Implications for Diabetic Retinopathy and Age-Related Retinal Diseases. JOJ OPHTHALMOLOGY 2021; 8:77-85. [PMID: 35187384 PMCID: PMC8856657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Diabetic retinopathy (DR) is a devastating disease leading to blindness among majority of working adults around the globe. Nonetheless, an effective treatment or cure for the disease is still to be achieved. This is because the cellular and molecular mechanisms of DR are complex and not fully understood yet. In this article, we describe how high glucose induced TXNIP upregulation and associated redox stress may cause mitochondrial dysfunction, mitophagy, ferritinophagy (iron release by autophagy) and lysosome destabilization. Labile irons react with hydrogen peroxide (H2O2) to generate hydroxyl radicals (.OH) by the Fenton reaction and cause membrane phospholipid peroxidation due to reduction in glutathione (GSH) level and glutathione peroxidase 4 (GPX4) activity, which cause ferroptosis, a recently identified non-apoptotic cell death mechanism. We used in this study a retinal pigment epithelial cell line, ARPE- 19 and exposed it to high glucose in in vitro cultures to highlight some of the intricacies of these cellular processes, which may be relevant to the pathogenesis of DR and age-related retinal neurodegenerative diseases, such as age-related macular degeneration, AMD.
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Affiliation(s)
- Lalit Pukhrambam Singh
- Corresponding author: Lalit Pukhrambam Singh, Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine Detroit, MI 48201, USA
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Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism. Biomedicines 2020; 8:biomedicines8110526. [PMID: 33266387 PMCID: PMC7700424 DOI: 10.3390/biomedicines8110526] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are of great relevance to health, and their dysregulation is associated with major chronic diseases. Research on mitochondria-156 brand new publications from 2019 and 2020-have contributed to this review. Mitochondria have been fundamental for the evolution of complex organisms. As important and semi-autonomous organelles in cells, they can adapt their function to the needs of the respective organ. They can program their function to energy supply (e.g., to keep heart muscle cells going, life-long) or to metabolism (e.g., to support hepatocytes and liver function). The capacity of mitochondria to re-program between different options is important for all cell types that are capable of changing between a resting state and cell proliferation, such as stem cells and immune cells. Major chronic diseases are characterized by mitochondrial dysregulation. This will be exemplified by cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, immune system disorders, and cancer. New strategies for intervention in chronic diseases will be presented. The tumor microenvironment can be considered a battlefield between cancer and immune defense, competing for energy supply and metabolism. Cancer cachexia is considered as a final stage of cancer progression. Nevertheless, the review will present an example of complete remission of cachexia via immune cell transfer. These findings should encourage studies along the lines of mitochondria, energy supply, and metabolism.
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Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers. Int J Mol Sci 2020; 21:ijms21176052. [PMID: 32842667 PMCID: PMC7504413 DOI: 10.3390/ijms21176052] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.
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