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Bharathidevi Subramaniam Rajesh, Aloysius Dhivya Manohar, Sulochana KN; Copper triggers mitochondrial biogenesis and helps in survival of RPE. Invest. Ophthalmol. Vis. Sci. 2018;59(9):343.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal pigment epithelial cell (RPE) dysfunction is the key factor in Age related macular degeneration (AMD). Decreased copper levels in serum and increased copper accumulation in RPE are reported in AMD subjects. Validation of copper supplementation as a therapy for AMD is under clinical trials. This study was done to understand the importance of copper in mitochondrial regulation in human retinal pigment epithelial cells - ARPE-19 cells
ARPE-19 cells were grown in normal glucose (5.5 mM) and exposed to copper from 50 μM to 400 μM for 24 h. The copper homeostasis was studied by analysing the influx and efflux chaperones as well as copper trafficking chaperones at mRNA and protein level. Copper uptake by ARPE-19 cells was estimated by Phen Green assay and AAS method. Cytochrome C Oxidase (COX) activity was done in cell lysates treated with copper. The mitochondrial biogenesis markers TFAM, PGC1β and VEGF was analysed by qPCR, western blot and ELISA. Mitochondrial mass was measured using Complex 1 DNA copy number. Statistical analysis were done using graph pad prism and p-values< 0.05 were considered significant.
Accumulation of copper inside the cell was significantly increased dose dependently correlating with copper transporter 1 and 2 influx chaperones (p≤0.05). The antioxidant chaperones ATOX 1 showed 6 fold and mitochondrial chaperone SCO1 showed 3 fold increase at 50 μM copper treatment.(COX) activity revealed 2 fold increase with copper treatment along with TFAM and PGC1β showing concomitant increase at 50 and 100 μM copper (p≤0.01) respectively at both mRNA and protein levels. The ERRα and VEGF levels also increased with copper treatment. We hypothesis that, copper trafficking via SCO1 to mitochondria increases COX activity and triggers mitochondrial biogenesis and helps in RPE survival.
This is the first report showing Copper stimulates mitochondrial biogenesis and cell survival by regulating PGC1beta - ERRalpha - VEGF aixs.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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