TY - JOUR
T1 - Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells
AU - Lee, Jong Jer
AU - Ishihara, Kenji
AU - Notomi, Shoji
AU - Efstathiou, Nikolaos E.
AU - Ueta, Takashi
AU - Maidana, Daniel
AU - Chen, Xiaohong
AU - Iesato, Yasuhiro
AU - Caligiana, Alberto
AU - Vavvas, Demetrios G.
N1 - Funding Information:
This work was supported by the Yeatts Family Foundation (D.G.V.); Monte J. Wallace (DGV) 2013 Macula Society Research Grant award (D.G.V.); a Physician Scientist Award by the Research to Prevent Blindness Foundation (D.G.V.); Robert Machemer Foundation Vitreoretinal Research Scholarship (SN); NEI R21EY023079-01/A1 (D.G.V.); NEI grant EY014104 (MEEI Core Grant); Loeffler Family fund (D.G.V.); R01EY025362-01 (D.G.V.); ARI Young investigator Award (D.G.V.); Foundation Lions Eye Research Fund (D.G.V.); NIH NEI Core grant P30EY003790 (D.G.V.)
Funding Information:
This work was supported by the Yeatts Family Foundation (D.G.V.); Monte J. Wallace (DGV) 2013 Macula Society Research Grant award (D.G.V.); a Physician Scientist Award by the Research to Prevent Blindness Foundation (D.G.V.); Robert Machemer Foundation Vitreoretinal Research Scholarship (SN); NEI R21EY023079-01/A1 (D.G.V.); NEI grant EY014104 (MEEI Core Grant); Loeffler Family fund (D.G.V.); R01EY025362-01 (D.G.V.); ARI Young investigator Award (D.G.V.); Foundation Lions Eye Research Fund (D.G.V.); NIH NEI Core grant P30EY003790 (D.G.V.) Appendix A
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/1/8
Y1 - 2020/1/8
N2 - Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.
AB - Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.
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U2 - 10.1016/j.bbrc.2019.10.138
DO - 10.1016/j.bbrc.2019.10.138
M3 - Article
C2 - 31672277
AN - SCOPUS:85074421524
SN - 0006-291X
VL - 521
SP - 414
EP - 419
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -