Mitochondrial outer membrane protein FUNDC2 contributes to ferroptosis as a potential upstream regulator in retinitis pigmentosa.
TL;DR
Findings provide the first evidence that FUNDC2 acts as a potential upstream regulator of RPE ferroptosis in RP, at least partially by negatively regulating GPX4.
Abstract
Aim
To investigate the key role of the mitochondrial outer membrane protein FUN14 domain-containing 2 (FUNDC2) in retinal pigment epithelium (RPE) ferroptosis during retinitis pigmentosa (RP) progression.
Methods
Unbiased label-free proteomics was employed to identify differentially expressed proteins in the RPE of a sodium iodate (SI)-induced rat model. In vitro experiments were conducted using human retinal pigment epithelial (ARPE)-19 cells. The effects of SI treatment and FUNDC2 knockdown on cell viability and the expression of ferroptosis-protective molecules, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 25 member 11 (SLC25A11) were evaluated.
Results
Proteomic analysis revealed that FUNDC2 was significantly upregulated in the RPE of SI-induced rats. In ARPE-19 cells, SI treatment significantly increased FUNDC2 expression while decreasing the levels of ferroptosis-protective molecules. Functional experiments demonstrated that knocking down FUNDC2 effectively rescued SI-induced loss of cell viability and restored GPX4 expression.
Conclusion
These findings provide the first evidence that FUNDC2 acts as a potential upstream regulator of RPE ferroptosis in RP, at least partially by negatively regulating GPX4. Consequently, FUNDC2 is a potential therapeutic target for the future treatment of RP.