Chorein deficiency promotes ferroptosis
Ferroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A de...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1002/2211-5463.13870 |
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| author | Yoshiaki Nishizawa Hitoshi Sakimoto Omi Nagata Natsuki Sasaki Yuka Urata Kaoru Arai Hanae Hiwatashi Izumi Yokoyama Shosei Kishida Akira Sano Masayuki Nakamura |
| author_facet | Yoshiaki Nishizawa Hitoshi Sakimoto Omi Nagata Natsuki Sasaki Yuka Urata Kaoru Arai Hanae Hiwatashi Izumi Yokoyama Shosei Kishida Akira Sano Masayuki Nakamura |
| author_sort | Yoshiaki Nishizawa |
| collection | DOAJ |
| description | Ferroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A deficiency in ferroptosis. The VPS13A gene encodes for chorein, and its deficiency is a molecular cause of chorea‐acanthocytosis (ChAc), a Huntington‐like disease with neurodegeneration in the striatum. In our previous study, we found male infertility characterized by increased malondialdehyde staining of the spermatozoa in the testes of the ChAc model mice. Thus, in this study we performed metabolome analysis of sperm extracted from the epididymis of the ChAc model mice, which revealed decreased cystine levels, suggesting an association between chorein deficiency and ferroptosis. We then investigated the role of chorein in ferroptosis using VPS13A knockdown (VPS13A‐KD) HEK293 cells. We found that VPS13A‐KD cells displayed a significantly diminished resistance to tert‐Butyl hydroperoxide (tBHP)‐induced lipid peroxidation and cell death compared to control cells, which could be rescued by treatment with ferrostatin‐1. Moreover, VPS13A‐KD cells showed Fe(II) accumulation, suggesting an impaired capacity for divalent iron removal. In the cytosolic fraction of VPS13A‐KD cells, the protein level of glutathione peroxidase 4 (GPX4) was significantly reduced, suggesting that dysfunction of chorein impairs GPX4 transport, thereby facilitating ferroptosis. These results suggest that ferroptosis may contribute to neurodegeneration in ChAc caused by loss of chorein function. |
| format | Article |
| id | doaj-art-a58b6a97f96f4fb79286ed0115c69d19 |
| institution | Kabale University |
| issn | 2211-5463 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj-art-a58b6a97f96f4fb79286ed0115c69d192025-01-07T02:27:34ZengWileyFEBS Open Bio2211-54632025-01-01151586810.1002/2211-5463.13870Chorein deficiency promotes ferroptosisYoshiaki Nishizawa0Hitoshi Sakimoto1Omi Nagata2Natsuki Sasaki3Yuka Urata4Kaoru Arai5Hanae Hiwatashi6Izumi Yokoyama7Shosei Kishida8Akira Sano9Masayuki Nakamura10Department of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanDepartment of Biochemistry and Genetics Kagoshima University Graduate School of Medical and Dental Sciences JapanKagoshima University JapanDepartment of Psychiatry Kagoshima University Graduate School of Medical and Dental Sciences JapanFerroptosis is a type of programmed cell death owed to an intracellular accumulation of iron resulting in the generation reactive oxygen species, which in turn can cause peroxidation of plasma membrane lipids and ultimately result in cell death. We investigated the potential involvement of VPS13A deficiency in ferroptosis. The VPS13A gene encodes for chorein, and its deficiency is a molecular cause of chorea‐acanthocytosis (ChAc), a Huntington‐like disease with neurodegeneration in the striatum. In our previous study, we found male infertility characterized by increased malondialdehyde staining of the spermatozoa in the testes of the ChAc model mice. Thus, in this study we performed metabolome analysis of sperm extracted from the epididymis of the ChAc model mice, which revealed decreased cystine levels, suggesting an association between chorein deficiency and ferroptosis. We then investigated the role of chorein in ferroptosis using VPS13A knockdown (VPS13A‐KD) HEK293 cells. We found that VPS13A‐KD cells displayed a significantly diminished resistance to tert‐Butyl hydroperoxide (tBHP)‐induced lipid peroxidation and cell death compared to control cells, which could be rescued by treatment with ferrostatin‐1. Moreover, VPS13A‐KD cells showed Fe(II) accumulation, suggesting an impaired capacity for divalent iron removal. In the cytosolic fraction of VPS13A‐KD cells, the protein level of glutathione peroxidase 4 (GPX4) was significantly reduced, suggesting that dysfunction of chorein impairs GPX4 transport, thereby facilitating ferroptosis. These results suggest that ferroptosis may contribute to neurodegeneration in ChAc caused by loss of chorein function.https://doi.org/10.1002/2211-5463.13870chorea‐acanthocytosischoreinferroptosisferrous ironglutathione peroxidase 4VPS13A |
| spellingShingle | Yoshiaki Nishizawa Hitoshi Sakimoto Omi Nagata Natsuki Sasaki Yuka Urata Kaoru Arai Hanae Hiwatashi Izumi Yokoyama Shosei Kishida Akira Sano Masayuki Nakamura Chorein deficiency promotes ferroptosis FEBS Open Bio chorea‐acanthocytosis chorein ferroptosis ferrous iron glutathione peroxidase 4 VPS13A |
| title | Chorein deficiency promotes ferroptosis |
| title_full | Chorein deficiency promotes ferroptosis |
| title_fullStr | Chorein deficiency promotes ferroptosis |
| title_full_unstemmed | Chorein deficiency promotes ferroptosis |
| title_short | Chorein deficiency promotes ferroptosis |
| title_sort | chorein deficiency promotes ferroptosis |
| topic | chorea‐acanthocytosis chorein ferroptosis ferrous iron glutathione peroxidase 4 VPS13A |
| url | https://doi.org/10.1002/2211-5463.13870 |
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