Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis

Abstract

Retinal pigment epithelium (RPE) degeneration plays an important role in a group of retinal disorders such as retinal degeneration (RD) and age-related macular degeneration (AMD). The mechanism of RPE cell death is not yet fully elucidated. Ferroptosis, a novel regulated cell death pathway, participates in cancer and several neurodegenerative diseases. Glutathione peroxidase 4 (GPx-4) and ferroptosis suppressor protein 1 (FSP1) have been proposed to be two main regulators of ferroptosis in these diseases; yet, their roles in RPE degeneration remain elusive. Here, we report that both FSP1-CoQ10-NADH and GSH-GPx-4 pathways inhibit retinal ferroptosis in sodium iodate (SIO)-induced retinal degeneration pathologies in human primary RPE cells (HRPEpiC), ARPE-19 cell line, and mice. GSH-GPx-4 signaling was compromised after a toxic injury caused by SIO, which was aggravated by silencing GPx-4, and ferroptosis inhibitors robustly protected RPE cells from the challenge. Interestingly, while inhibition of FSP1 caused RPE cell death, which was aggravated by SIO exposure, overexpression of FSP1 effectively protected RPE cells from SIO-induced injury, accompanied by a significant down-regulation of CoQ10/NADH and lipid peroxidation. Most importantly, in vivo results showed that Ferrostatin-1 not only remarkably alleviated SIO-induced RPE cell loss, photoreceptor death, and retinal dysfunction but also significantly ameliorated the compromised GSH-GPx-4 and FSP1-CoQ10-NADH signaling in RPE cells isolated from SIO-induced RPE degeneration. These data describe a distinct role for ferroptosis in controlling RPE cell death in vitro and in vivo and may provide a new avenue for identifying treatment targets for RPE degeneration.

Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders

“…Ferroptosis is regulated by numerous pathways and implicated in many diseases. In addition to the mechanisms mentioned above, there are other possible mechanisms which have been proposed, such as the antioxidant mechanisms which include GPX4 pathway [36], FSP1 pathway [37], and other pathways. FSP1-NADPH-CoQ pathway [38] and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway are potential regulatory pathways of ferroptosis [39].…”

Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice

“…It has been proven that TBI-induced neuronal necrosis and parenchymal hemorrhage release a large amount of free iron into the peripheral space, which further leads to ferroptosis due to excessive oxidative damage to neurons and glial cells [ 7 , 8 ]. Increased levels of antioxidant factors exert protective roles against ferroptosis [ 9 , 10 ], further indicating that ferroptosis is closely related to the disturbance of cellular redox homeostasis. Recent studies, including our own, have indicated that ferroptosis plays an important role in neuronal death and neural dysfunction after TBI [ 11 , 12 , 13 ], intracerebral hemorrhage [ 14 ], and spinal cord injury [ 15 ].…”

Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications

“…In addition, Zhang et al (2022b) reported that CoQ10 could improve oxidative stress, as indicated by the increased MDA concentration. Another report by Yang et al supported the functional regulatory effects of CoQ10 in ferroptosis, controlling sodium iodate-induced pathologies in vitro and in vivo (Yang et al, 2022b). However, the efficacy of CoQ10 as a ferroptosis-modulating agent against musculoskeletal disorders is not yet fully elucidated.…”