Molecular biology reports · 2026
Endolysosomal iron-associated vesicular changes and ferroptosis-related vulnerability in VPS13A-knockdown cells.
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Imamura Kensuke, Nishizawa Yoshiaki, Sainohira Kazutaka, Sakimoto Hitoshi, Urata Yuka, Sasaki Natsuki, Arai Kaoru, Hiwatashi Hanae, Yokoyama Izumi, Sano Akira, Nakamura Masayuki
Аннотация
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.
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.