Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells
IntroductionNeurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-01-01
|
| Series: | Frontiers in Nutrition |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnut.2023.1054852/full |
| _version_ | 1797948268809814016 |
|---|---|
| author | Emily F. Bengson Cole A. Guggisberg Thomas W. Bastian Michael K. Georgieff Moon-Suhn Ryu Moon-Suhn Ryu |
| author_facet | Emily F. Bengson Cole A. Guggisberg Thomas W. Bastian Michael K. Georgieff Moon-Suhn Ryu Moon-Suhn Ryu |
| author_sort | Emily F. Bengson |
| collection | DOAJ |
| description | IntroductionNeurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol.MethodsHere we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy via functional analysis of the omics profile of HT22 cells deficient in NCOA4.ResultsNCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted.DiscussionThese findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases. |
| first_indexed | 2024-04-10T21:40:40Z |
| format | Article |
| id | doaj.art-b440c96935db4f0eb2ce3be21c56ad4b |
| institution | Directory Open Access Journal |
| issn | 2296-861X |
| language | English |
| last_indexed | 2024-04-10T21:40:40Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Nutrition |
| spelling | doaj.art-b440c96935db4f0eb2ce3be21c56ad4b2023-01-19T05:11:25ZengFrontiers Media S.A.Frontiers in Nutrition2296-861X2023-01-011010.3389/fnut.2023.10548521054852Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cellsEmily F. Bengson0Cole A. Guggisberg1Thomas W. Bastian2Michael K. Georgieff3Moon-Suhn Ryu4Moon-Suhn Ryu5Department of Food Science and Nutrition, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, Saint Paul, MN, United StatesDepartment of Food Science and Nutrition, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, Saint Paul, MN, United StatesDepartment of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN, United StatesDepartment of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN, United StatesDepartment of Food Science and Nutrition, College of Food, Agricultural and Natural Resource Sciences, University of Minnesota, Saint Paul, MN, United StatesDepartment of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Republic of KoreaIntroductionNeurons require iron to support their metabolism, growth, and differentiation, but are also susceptible to iron-induced oxidative stress and cytotoxicity. Ferritin, a cytosolic iron storage unit, mediates cellular adaptation to fluctuations in iron delivery. NCOA4 has been characterized as a selective autophagic cargo receptor facilitating the mobilization of intracellular iron from ferritin. This process named ferritinophagy results in the degradation of ferritin and the consequent release of iron into the cytosol.MethodsHere we demonstrate that NCOA4 is important for the adaptation of the HT22 mouse hippocampal neuronal cell line to cellular iron restriction. Additionally, we determined the pathophysiological implications of impaired ferritinophagy via functional analysis of the omics profile of HT22 cells deficient in NCOA4.ResultsNCOA4 silencing impaired ferritin turnover and was cytotoxic when cells were restricted of iron. Quantitative proteomics identified IRP2 accumulation among the most prominent protein responses produced by NCOA4 depletion in HT22 cells, which is indicative of functional iron deficiency. Additionally, proteins of apoptotic signaling pathway were enriched by those responsive to NCOA4 deficiency. Transcriptome profiles of NCOA4 depletion revealed neuronal cell death, differentiation of neurons, and development of neurons as potential diseases and bio functions affected by impaired ferritinophagy, particularly, when iron was restricted.DiscussionThese findings identify an integral role of NCOA4-mediated ferritinophagy in the maintenance of iron homeostasis by HT22 cells, and its potential implications in controlling genetic pathways of neurodevelopment and neurodegenerative diseases.https://www.frontiersin.org/articles/10.3389/fnut.2023.1054852/fullferritinophagyproteomicsRNA-seqferritiniron deficiencyIRP2 |
| spellingShingle | Emily F. Bengson Cole A. Guggisberg Thomas W. Bastian Michael K. Georgieff Moon-Suhn Ryu Moon-Suhn Ryu Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells Frontiers in Nutrition ferritinophagy proteomics RNA-seq ferritin iron deficiency IRP2 |
| title | Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells |
| title_full | Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells |
| title_fullStr | Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells |
| title_full_unstemmed | Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells |
| title_short | Quantitative omics analyses of NCOA4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal HT22 cells |
| title_sort | quantitative omics analyses of ncoa4 deficiency reveal an integral role of ferritinophagy in iron homeostasis of hippocampal neuronal ht22 cells |
| topic | ferritinophagy proteomics RNA-seq ferritin iron deficiency IRP2 |
| url | https://www.frontiersin.org/articles/10.3389/fnut.2023.1054852/full |
| work_keys_str_mv | AT emilyfbengson quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells AT coleaguggisberg quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells AT thomaswbastian quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells AT michaelkgeorgieff quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells AT moonsuhnryu quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells AT moonsuhnryu quantitativeomicsanalysesofncoa4deficiencyrevealanintegralroleofferritinophagyinironhomeostasisofhippocampalneuronalht22cells |