Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases

Abstract

Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases.

FIGURE 1

The physiological role of NCOA4. NCOA4 is composed of multiple splice variants in animals, whereas only two transcript variants in humans, involving NCOA4α (614 Aa, 70 kDa) and NCOA4β (286 Aa, 35 kDa). FTH1 combines with the C‐terminal domain in NCOA4 through a direct interaction of conserved surface arginine in NCOA4α. In consideration of NCOA4 specifically recognising FTH1 rather than FTL, the stored iron thereby converted into a mixture of FTH1–FTL that revealed a conformational transformation in the composition of ferritin complexes. The functional activation of NCOA4 is dependent on the interaction with another molecular called HERC2, which mainly targets the proteasome by virtue of structural destruction. HERC2, a large multidomain homologous to E6AP carboxy terminus (HECT) E3 ubiquitin ligase, can bind with NCOA4 for dynamic autophagy process when iron levels are high and subsequently drive close contact with NCOA4‐ferritin complex after ferritinophagy initiation to maintain functional stability. In the condition of cellular iron deficiency, HERC maintains a monosome instead of interacting with NCOA4. The high level of NCOA4 then triggers ferritinophagy, and subsequently increases cellular iron overload. Indeed, the HERC2 region spanning amino acids from 2292 to 2923 chelates NCOA4 more specifically in iron‐replete conditions than in iron‐chelated conditions. HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2; FTH1/FTL, ferritin heavy and light chains; NCOA4, nuclear receptor coactive 4.

FIGURE 2

NCOA4 mediates ferritin transport into the lysosome for degradation. During iron utilisation, ferritin can be dissociated from conjoint pores with the help of a small proteasome complex. Depending on PCBP1, Fe is combined with NCOA4 and ferritin to balance iron homeostasis. Double‐membrane vesicles can be constituted in the hyperdynamic phase by coordinating with Atg proteins, which phagocytise cellular cargo, eventually leading to lysosomal degradation. Ferroportin‐regulated iron exportation facilitates ferritin degradation via the proteasome whereas iron chelation inclines to lysosomal degradation. Atg, autophagy‐related gene; NCOA4, nuclear receptor coactive 4; PCBP1, poly rC‐binding protein 1.

FIGURE 3

NCOA4 mediates the release of ferritin iron to promote erythropoiesis. Intracellular iron can be transported to RBC with the help of Tf and Tf‐mediated endocytosis, followed by being reduced to Fe(II) form. Along with ferritin, iron is directly delivered to mitochondrion for heme synthesis or provisionally stored in LIP, accompanied by being degraded in the lysosome and eventually driven to mitochondrion for multifunctional biology. PCBP1 and NCOA4 coordinate to supply heme synthesis with sufficient iron via ferritin and ferritinophagy at the early stage of erythroblast. During the late phage of erythrocyte, levels of iron import together with ferritins markedly decrease, and iron in endosomes might be transferred to mitochondria for heme synthesis. HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2; LIP, labile iron pool; NCOA4, nuclear receptor coactive 4; PCBP1, poly rC‐binding protein 1; RBC, red blood cell; Tf, transferrin.

FIGURE 4

The molecular mechanisms underlying NCOA4‐mediated ferritinophagy in ferritinophagy–ferroptosis axis. NCOA4 refers to ferritinophagy receptor that combined with C terminal of FTH, accounting for the initiation of selective autophagy, special degradation of ferritin and enhanced bioavailability of cytosol iron. NCOA4 can interact with HERC2 to mediate ubiquitination and initiation of autophagic degradation to transport ferritin into lysosomes. As a result of accumulated Fe²⁺ induced by upregulated expression of NCOA4 in ferritinophagic response, the consequent downstream signalling cascades are implicated with cytomembrane destruction and even ferroptotic cell death. In detail, NCOA4‐mediated ferritnophagy and ferritinophagy–ferroptosis axis are involved in human diseases. Elevated level of redox‐active iron owning to transferrin hyperactivation may contribute to abnormal ferritin synthesis in human diseases. FTH1/FTL, ferritin heavy and light chains; HIF‐1α, hypoxia‐inducible factor‐1α; HO‐1, heme oxygenase‐1; HSF1, heat shock factor 1; NCOA4, nuclear receptor coactive 4; NRF2, nuclear factor erythroid2‐related factor 2; ROS, reactive oxygen species.