Analyzing the role of ferroptosis in ribosome-related bone marrow failure disorders: From pathophysiology to potential pharmacological exploitation

Abstract

Within the last decade, the scientific community has witnessed the importance of ferroptosis as a novel cascade of molecular events leading to cellular decisions of death distinct from apoptosis and other known forms of cell death. Notably, such non- apoptotic and iron-dependent regulated cell death has been found to be intricately linked to several physiological processes as well as to the pathogenesis of various diseases. To this end, recent data support the notion that a potential molecular connection between ferroptosis and inherited bone marrow failure (IBMF) in individuals with ribosomopathies may exist. In this review, we suggest that in ribosome-related IBMFs the identified mutations in ribosomal proteins lead to changes in the ribosome composition of the hematopoietic progenitors, changes that seem to affect ribosomal function, thus enhancing the expression of some mRNAs subgroups while reducing the expression of others. These events lead to an imbalance inside the cell as some molecular pathways are promoted while others are inhibited. This disturbance is accompanied by ROS production and lipid peroxidation, while an additional finding in most of them is iron accumulation. Once lipid peroxidation and iron accumulation are the two main characteristics of ferroptosis, it is possible that this mechanism plays a key role in the manifestation of IBMF in this type of disease. If this molecular mechanism is further confirmed, new pharmacological targets such as ferroptosis inhibitors that are already exploited for the treatment of other diseases, could be utilized to improve the treatment of ribosomopathies.

Keywords: anemia; bone marrow‐failure disorders; ferroptosis; hematopoiesis; iron metabolism; pharmacology; ribosomopathies.

FIGURE 1

Orchestrated accumulation process of iron within the organism. Iron absorbed by food has two forms: Non‐heme iron and heme iron. Non‐heme iron (Fe³⁺) is reduced to Fe²⁺ (ferrous) via DCYTB and further transported in the cell through DMT1 to join the LIP. In parallel, heme iron is transferred within the cell via the HCP1 and ferrous iron is released in the cell via HOX1 to join the LIP. Consequently, PCBP1 transfers ferrous iron to ferritin and vice versa, while it also delivers Fe²⁺ to FPN1 to export it in the cardiovascular system. Fe²⁺ is converted to Fe³⁺ (ferric) through hephaestin to interact with transferrin. This complex binds to TfR1 on the surface of the targeted cells. Furthermore, ferrous iron may enter into mitochondria for heme biosynthesis and generation of Fe‐S clusters. Subsequently, heme exports from mitochondria and the cell through the FLVCR. The exported heme molecules interact with hemopexin leading to the synthesis of heme‐hemopexin complex. This complex can be absorbed from hepatocytes and macrophages through the CD91 (this image was created with BioRender.com).

FIGURE 2

Schematic presentation of molecular mechanisms of ferroptosis. The major pathways involved in ferroptosis can be attributed to the interplay between the antioxidant defense system, represented by system Xc⁻, the FSP1‐CoQ10 and DHODH‐CoQ10 axis, MBOAT1/2‐MUFA axis, SC5D‐7‐DHC axis, GCH1‐BH4 axis, and the oxidative stress pathways, encompassing iron metabolism and lipid metabolism. First, system Xc⁻ facilitates the uptake of cysteine and its conversion into cysteine, which subsequently contributes to the synthesis of GSH. GSH interacts with GPX4 to neutralize lipid reactive oxygen species. Second, FSP1 and DHODH convert CoQ10 enzyme into its reduced form, CoQ10H2, which aids in the detoxification of lipid reactive oxygen species. Moreover, MBOAT1/2, increase the intracellular level of PE‐MUFAs while decreasing the level of PE‐PUFAs, which are the main substrate for lipid peroxidation. Another antioxidant pathway is SC5D‐7‐DHC axis, in which 7‐DHC acts as a free radical trapping agent and protect cells from lipid peroxidation, while in the GCH1‐BH4 axis, BH4 alone and synergistically with a‐TOH also act as free radical trapping agents. Furthermore, lipid metabolism, PUFAs present in the plasma membrane interact with ACSL4, LPCAT3, and ALOXs, resulting in the generation of lipid reactive oxygen species. Additionally, Iron metabolism plays an important role in ferroptosis. Through the TfR1, Fe³⁺ is internalized and subsequently reduced to Fe²⁺. Subsequently, Fe²⁺ contributes to the formation of the LIP and reacts with hydrogen peroxide (H₂O₂) via the Fenton reaction, leading to the production of lipid reactive oxygen species. Excess intracellular iron is sequestered within ferritin, while the remaining iron is exported through FPN (this image was created with BioRender.com).

FIGURE 3

Diagrammatic depiction of “specialized ribosomes.” Ribosome heterogeneity can occur through differentiated levels of RPs or/and rRNAs composition, RP paralogs, ribosome‐associated factors (RAPs) and rRNA modifications (this image was created with BioRender.com).

FIGURE 4

Diagrammatic depiction of ferroptosis as a potential mechanism of Diamond–Blackfan anemia (DBA) and 5q− syndrome in HSCs, according to existing experimental data. In DBA, low expression of ribosomal proteins (especially the RPS19) and in 5q− syndrome, low expression most usually the RPS14, leads to reduced and impaired ribosomes. Ribosomes reduction appears to limit the globin genes expression and further hemoglobin levels. Consequently, the low levels of hemoglobin, combined with decreased levels of the heme exporter FLVCR1, result in heme accumulation and increased levels of intracellular lipid reactive oxygen species. Furthermore, both syndromes exhibit reduced expression of the subunit SLC7A11, one of the two subunits of the system Xc⁻. SLC7A11 reduction seems to decrease GSH synthesis, which is essential for the detoxification of lipid reactive oxygen species through the action of GPX4 (this image was created with BioRender.com).

FIGURE 5

Illustration of the potential connection between SDS and ferroptosis in bone marrow cells, according to existing experimental data. The reduction in the expression of SBDS gene leads to impaired 60S formation, subsequently resulting in impaired ribosomes. This reduction in ribosomes seems to decrease the RARα expression. RARα has been associated with the upregulation of GPX4 and FSP1, which are antioxidant molecules crucial for the detoxification of intracellular ROS and for cell resistance to ferroptosis. Therefore, the downregulation of RARα in SDS may potentially affect the expression of these antioxidant molecules, compromising the cellular defense against ferroptosis. Moreover, increased NOX4, CYGB and TfR2, all associated with high levels of intracellular ROS and ferroptosis, have been observed in SBDS‐silenced cells. High levels of TfR2 may increase the intracellular iron and subsequently increase the production of lipid reactive oxygen species through the Fenton reaction (this image was created with BioRender.com).

FIGURE 6

Depiction of the potential pathways connecting X‐linked dyskeratosis congenita (DC) and cartilage hair hypoplasia (CHH) with ferroptosis. Existing data suggests that reduced expression of RMRP and DKC1 results in low levels of TERT and TERC, respectively. TERT and TERC play crucial roles in telomerase activity, and their diminished expression leads to increased levels of intracellular ROS. Previous studies have already established the association between TERC, TERT, and ferroptosis. Furthermore, the decreased expression of DKC1 leads to reduced levels of CBPB and genes related to GSH metabolism. These genes are involved in various antioxidant pathways, including FSP1, NRF‐2, and GPX4 pathways. Low levels of CBPB and GSH‐related genes may disrupt these pathways, resulting in intracellular ROS accumulation and rendering cells more susceptible to ferroptosis (this image was created with BioRender.com).