Language：Japanese   Publisher：Molecular Biology Reports  

Background: Chorein, the VPS13A gene product whose loss causes chorea-acanthocytosis (ChAc, VPS13A disease), has been implicated in ferroptosis-related vulnerability, but the organellar basis of this phenotype remains unclear. Using VPS13A knockdown (VPS13A-KD) human embryonic kidney 293 (HEK293) cells, we previously found that chorein reduction is associated with impaired ferrous iron (Fe(II)) efflux, increased lipid peroxidation, reduced glutathione peroxidase 4 (GPX4) levels in the cytosolic fraction, and ferrostatin-1–suppressible cell death. Methods and results: In this study, we found that VPS13A-KD cells exhibited significantly elevated lipid peroxidation following treatment with the oxidant tert-butyl hydroperoxide (tBHP), and this increase was markedly suppressed by the iron chelator deferasirox (DFX) or the antioxidant vitamin E (α-tocopherol). DFX treatment induced enlarged vesicular structures in VPS13A-KD cells, showing spatial overlap of Fe(II), lipid peroxidation, and lysosomal signals, suggesting altered vesicular responses to oxidative stress. These enlarged vesicles showed partial spatial overlap with the late endosomal marker RAB7A, consistent with involvement of the late endosomal–lysosomal system. VPS13A-KD cells also exhibited mitochondrial morphological abnormalities, and a subset of enlarged vesicles overlapped with the mitochondrial outer membrane protein TOMM20, suggesting altered interactions between mitochondria and endolysosomal compartments. Conclusions: These findings suggest that lysosome-associated vesicular changes in VPS13A-KD cells may be associated with altered iron handling, consistent with our previous finding of impaired Fe(II) efflux. Although DFX reduced lipid peroxidation, it was also associated with prominent vesicular alterations, the significance of which remains to be clarified. In contrast, α-tocopherol attenuated oxidative injury without prominent vesicular accumulation in this model.

DOI： 10.1007/s11033-026-12649-2

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Language：Japanese   Publisher：FEBS Open Bio  

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.

DOI： 10.1002/2211-5463.13870

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Language：English   Publishing type：Research paper (scientific journal)  

Publisher：Neurology: Genetics  

DOI： 10.1212/NXG.0000000000000332

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Publisher：Neurology: Genetics  

DOI： 10.1212/NXG.0000000000000328

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Publisher：Journal of Human Genetics  

DOI： 10.1038/s10038-020-00867-w

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