NPC1 Deficiency Contributes to Autophagy-Dependent Ferritinophagy in HEI-OC1 Auditory Cells

Abstract

Niemann–Pick type C disease (NPCD) is a rare genetic syndrome characterized by cholesterol accumulation in multiple organelles. NPCD is mainly caused by gene deficiency of NPC intracellular cholesterol transporter 1 (NPC1). It has been reported that some of the NPCD patients exhibit clinical features of progressive hearing loss at high frequency and iron disorder, but the underlying relationship is unknown. A recent study has reported that ferroptosis contributes to the impairment of cochlear hair cells that are related to sensory hearing. In this study, we generated NPC1-deficient HEI-OC1 cells to show the effect of NPC1 deficiency on cochlear outer hair cells. We found that NPC1 deficiency enhances autophagy-dependent ferritinophagy to release Fe (II). Our work provides important insights into the effect of NPC1 deficiency in auditory cells, indicating that it induces ferroptosis and results in hearing loss.

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

“…Gene ontology (GO) analysis on biological processes showed an enrichment in proteins related to vesicle and vacuole fusion and organization, ion homeostasis and transport (namely, iron, manganese, and calcium), polyphosphate metabolism, Golgi organization, autophagy, and protein targeting to vacuole ( Figure 2 D and Supplementary Table S3 ). These results suggest that vesicle trafficking pathways and ion homeostasis are altered in yeast cells lacking Ncr1, being consistent with previously reported trafficking defects and calcium/iron dyshomeostasis [ 9 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 42 , 43 , 44 , 46 , 47 , 58 ] and alterations in the expression of lysosomal proteins related to autophagy in NPC [ 27 ]. A previous study with the yeast model also showed that Ncr1 interacts with vacuolar proteins, including the Pmc1 Ca 2+ ATPase and the Fth1 iron transporter.…”

“…NPC1 fibroblasts from patients also exhibit enhanced expression of genes encoding proteins involved in iron homeostasis (ferritin and sideroflexin 1) [ 70 ]. However, several studies report a ferritin deficiency in various NPC tissues [ 44 , 46 , 71 , 72 ] and a decrease in FTH1 (H-ferritin) protein levels in NPC1-deficient HeLa cells [ 47 ]. It has been proposed that lower levels of ferritin lead to an excess of unbound iron, thus favoring lipid peroxidation caused by reactive oxygen species (ROS) [ 73 ].…”

“…Mitochondrial dysfunction in NPC has also been associated with calcium cytotoxicity resulting from the activation of the IP3R type 1 in the ER that increases calcium release [ 41 ]. Numerous studies have also shown that iron homeostasis is disrupted in the plasma and tissues of NPC patients and in animal and cell models of this disease [ 42 , 43 , 44 , 45 , 46 , 47 ]. Iron is a redox-active metal that catalyzes the Fenton reaction, in which hydrogen peroxide is converted into highly reactive hydroxyl radicals.…”

The role of receptor‐type protein tyrosine phosphatases in cancer

“…Ferroptosis is a form of regulated cell death implicated in cancer context. It is induced by iron‐dependent lipid peroxides accumulation that results in oxidative damage 123–125 . Besides redox homeostasis factors, ferroptosis is also regulated by various signaling pathways including Wnt/beta‐catenin signaling, PI3K‐AKT signaling, and JAK–STAT pathway.…”

“…It is induced by iron-dependent lipid peroxides accumulation that results in oxidative damage. [123][124][125] Besides redox homeostasis factors, ferroptosis is also regulated by various signaling pathways including Wnt/beta-catenin signaling, PI3K-AKT signaling, and JAK-STAT pathway. It is reported that the activation of the Wnt/betacatenin signaling caused ferroptosis resistance by targeting GPX4 in gastric cancer.…”