Metabolite and protein shifts in mature erythrocyte under hypoxia

Abstract

As the only cell type responsible for oxygen delivery, erythrocytes play a crucial role in supplying oxygen to hypoxic tissues, ensuring their normal functions. Hypoxia commonly occurs under physiological or pathological conditions, and understanding how erythrocytes adapt to hypoxia is fundamental for exploring the mechanisms of hypoxic diseases. Additionally, investigating acute and chronic mountain sickness caused by plateaus, which are naturally hypoxic environments, will aid in the study of hypoxic diseases. In recent years, increasingly developed proteomics and metabolomics technologies have become powerful tools for studying mature enucleated erythrocytes, which has significantly contributed to clarifying how hypoxia affects erythrocytes. The aim of this article is to summarize the composition of the cytoskeleton and cytoplasmic proteins of hypoxia-altered erythrocytes and explore the impact of hypoxia on their essential functions. Furthermore, we discuss the role of microRNAs in the adaptation of erythrocytes to hypoxia, providing new perspectives on hypoxia-related diseases.

Keywords: Biochemistry; Biophysics.

Graphical abstract

Figure 1

Skeleton structure of erythrocyte membrane Magnifying the erythrocyte membrane from the area of the blue square, it can be seen that the surface of the erythrocyte membrane is supported by a hexagonal-like network skeleton. The sides of the hexagon are made up of spectrin tetramers, and the end and midpoints of each side are covered by gray ovals and semi-transparent yellow circles, respectively. When zooming in further, the gray oval, representing the spectrin-actin junction complex, anchors the ends of the spectrin tetramer to the cell membrane. The semi-transparent yellow circle, which represents the band 3/ankyrin 1 protein complex, can anchor the spectrin tetramer to the cell membrane from the middle.

Figure 2

Hypoxia affects the deformability of erythrocyte membrane (A) Competition of deoxyHb with ankyrin for band 3 reduces erythrocyte membrane deformability by separating the cytoskeleton from the membrane. (B) The way of NO production under different hypoxia levels and its multiple effects on erythrocyte membrane deformability. (C) Hypoxia leads to the release of Mg²⁺ bound to deoxyHb, which makes band 3 more susceptible to phosphorylation. The phosphorylated band 3 detaches from the cytoskeleton to form mobile band 3, which further aggregates into clusters, resulting in a decrease in erythrocyte membrane deformability. (D) Hypoxia causes changes in the number and activity of enzymes on the cell membrane resulting in a decrease in the deformability of the erythrocyte membrane.

Figure 3

Hypoxia affects adenosine signaling pathways in erythrocytes (A) AMPK-BPGM signaling pathway. (B) ADOA2B-PKA signaling pathway.