Red Blood Cell Metabolism

• Understanding the general structural and functional features of red blood cells (RBCs) is an objective.
• Recognizing the main metabolic pathways occurring in RBCs with reference to their relations to functions of RBCs is important.
• Identifying main and common diseases of RBCs as implication of defects of RBCs metabolism is necessary.

RBC Characteristics

• RBCs lack a nucleus, meaning they have no nucleic acids, DNA, or RNA.
• RBCs cannot reproduce and do not contain cell organelles like mitochondria, Golgi apparatus, endoplasmic reticulum, ribosomes, or lysosomes.
• RBCs have no synthetic activities like protein, lipid, or carbohydrate synthesis.
• Mature RBCs cannot generate energy (ATP) through the Krebs cycle because they lack mitochondria.
• Glucose is the primary energy source for RBCs.
• Biochemical energy-producing pathways available include glycolysis, the pentose-phosphate pathway and glutathione reduction.
• Red blood cells circulate for approximately 120 days.
• Red blood cell disorders include anemia, polycythemia, and hemolysis.

RBC Metabolism

• RBCs lack mitochondria and therefore cannot perform oxidation of fatty acids/ketone bodies, the citric acid cycle (CAC), or use the respiratory chain (electron transport chain). Energy in the form of ATP is obtained only from the glycolytic breakdown of glucose with the production of lactate at 2 ATP via anaerobic glycolysis.
• ATP generated is used to maintain the biconcave shape of RBCs and regulate the transport of ions & water in and out of RBCs.
• Glucose is transported through the RBC membrane by facilitated diffusion via glucose transporters-1 (GLUT-1), independent of insulin.

Anaerobic Glycolysis

• Glucose is metabolized in RBCs through anaerobic glycolysis, which does not require mitochondria or oxygen.
• One molecule of glucose yields 2 ATP molecules through one anaerobic glycolytic pathway.
• Two molecules of lactate are produced.
• Lactate is transported to the blood and converted back to glucose in the liver.

Importance of Glycolysis

• ATP energy production: Glycolysis is the only pathway that supplies red cells with ATP.
• NADH for Reduction of methemoglobin: Glycolysis provides NADH for the reduction of metHb by cytochrome b5 reductase
• 2,3 bisphosphoglycerate (2,3 BPG) binds to Hb to decreases its affinity for O2, and helps its availability to tissues.
• In RBCs, glycolysis pathways are modified for 2,3-Bisphosphoglycerate formation. This is done by bisphosphoglycerate mutase.
• (2, 3 BPG) binds to DeoxyHb to stabilize the tense state (T state) of Hb, decreasing hemoglobin's affinity for oxygen, favoring the release of O2 to peripheral tissues.
• As a result of BPG, oxyhemoglobin unloads oxygen better.
• 2,3-BPG becomes depleted in stored blood, so the R state of Hb is stabilized.
• If BPG depleted blood is used for a transfusion, the R-state Hb doesn't release O2.
• Adding inosine to stored blood maintains BPG levels.
• 2,3-DPG is a primary regulator of hemoglobin-O2 affinity.

Genetic Defects

• Genetic defects in glycolytic enzymes result in a reduced rate of glycolysis in RBCs, depriving them of ATP.
• This can result in congenital chronic hemolytic anemia, where RBCs cannot maintain their biconcave shape to squeeze through capillaries.
• This results in hemolysis (destruction of RBCs), with blood films showing dysmorphic RBCs called echinocytes.
• 95% of genetic defects in glycolytic enzymes are caused by pyruvate kinase deficiency.
• Important Clinical Disorders in Glycolysis include:
  • Pyruvate Kinase Deficiency
  • Hexokinase Deficiency

RBC Membrane Structure

• RBCs need be able to squeeze through tight spots in microcirculation (capillaries) easily and reversibly.
• RBC membranes are fluid and flexible.
• RBC membranes comprise a lipid bilayer, determining fluidity, and proteins that determine flexibility.
• Proteins are either peripheral or integral, penetrating the lipid bilayer, and carbohydrates are only on the external surface.
• The membrane skeleton consists of four structural proteins: spectrin, ankyrin, protein 4.1, and actin.
• Defects of proteins lead to abnormalities of shape of RBCs membrane as in cases of hereditary spherocytosis.

Congenital Hemolytic Anemia

• This can be caused by:
• Cell Membrane Disorders: Hereditary Spherocytosis (HS)
• Enzyme Deficiencies: G6PD Deficiency
• Hemoglobin Disorders: Globin deficiency (Thalassemia) and Globin abnormalities (Sickle cell anemia).

Pentose Phosphate Pathway

• The pentose phosphate pathway (PPP) or hexose monophosphate pathway (HMP) is an oxidative pathway for glucose occurring in the cytosol of many cells, including RBCs.
• In RBCs the pathway does not produce ATP.
• NADPH production: PPP is the only source for NADPH in RBCs.
• Ribose-5-phosphate production for adenine nucleotide synthesis.
• Important uses include:
• Lipids Synthesis: Important for fatty acids, cholesterol, steroids & sphingolipids
• Methemoglobin Reduction: via NADPH methemoglobin reductase
• Nitric oxide Synthesis
• Phagocytosis by oxygen-dependent by WBCs (macrophages)
• Antioxidant Mechanisms (part of Glutathione system )
• NADPH reduces oxidized glutathione, thus glutathione is needed in reduced form mostly.
• Glucose 6-phosphate dehydrogenase deficiency (G6PD Deficiency) is caused by deficiency of the first enzyme of pentose phosphate pathway (PPP).
• The deficiency leads to reduced production of NADPH ending in Acute Hemolytic Anemia

Explore red blood cell (RBC) metabolism, focusing on ATP production, glycolysis, and glucose transport. Learn about the importance of anaerobic glycolysis, the absence of mitochondria, and the Cori cycle. Test your knowledge of RBC metabolic pathways.