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If red blood cells have no mitochondria how are they able to metabolize glucose?

If red blood cells have no mitochondria how are they able to metabolize glucose?


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I have read that red blood cells (RBCs) metabolize glucose. However they don't have any mitochondria because there is just so much hemoglobin that there is no room for mitochondria without expanding the cell.

So how is it possible for them to metabolize glucose if it is mainly O2, CO2, H2O, fatty acids (in cell membrane), and hemoglobin?


In humans (and all mammals), red blood cells lack mitochondria and therefore has no functional TCA cycle. They metabolize glucose mainly via glycolysis, forming lactate which is released from the cells; this yields 2 ATP for each glucose molecule, much less than complete oxidation (ca 30 ATP), but enough to support the red blood cells' energy needs.

There is some oxidation of glucose to CO2 in red blood cells though. This occurs mainly in the pentose phosphate pathway or "shunt", where 1 carbon of glucose is released as CO2, and the energy extracted is used to reduce NADP to NADPH, which functions as an antioxidant. The resulting 5-carbon sugars (pentoses) are then rearranged to a 3-carbon sugar (glyceraldehyde phosphate) which enter glycolysis again. Hence the term "shunt": 5/6 of the glucose carbon that enter actually comes back to glycolysis again.

By varying flux through the PPP, cells can balance the use of glucose for ATP (energy) or NADPH (antioxidant). Studies estimate that in human red blood cells, 10--30% of hexokinase flux is diverted through the PPP, and the remainder through upper glycolysis (see this and this article). This corresponds to 2--5% of glucose carbon released as CO2, and the remainder metabolized to lactate.

Note that the above apply to mammalian red blood cells. Red cells of other vertebrates, including birds and fish, retain both their nucleus and mitochondria, and their metabolism is different.


While hemoglobin makes up about 90% of the protein in an RBC, there are many other proteins present as well, including enzymes in the anaerobic pentose phosphate pathway, which is responsible for metabolizing about 90% of the glucose entering the cell (the aerobic pathway takes care of the other 10%). There are also proteins responsible for maintaining the oxidation state of the hemoglobin-bound iron atoms. The iron in oxidized hemoglobin, or methemoglobin is in the $Fe^{3+}$ (ferric) state, which is unable to bind oxygen. The NADH-dependent enzyme methemoglobin reductase converts the iron to the $Fe^{2+}$ ferrous state, which binds $O_2$. NADH just happens to be one of the most important products of the pentose phosphate pathway, along with ATP and 2,3-BPG, which helps regulate $O_2$ release from hemoglobin. NADPH is also produced by the anaerobic pathway, and is a cofactor in the reduction of oxidized glutathione, acting as one of the major reducing agents in the cell to protect against oxidative stress. Other enzymes such as superoxide dismutase, glutathione peroxidase, and catalase also help prevent or reverse oxidation. All of the oxygen moving to and fro results in the formation of reactive oxygen species such as superoxide and hydroperoxyl radicals ($cdot{O_2^-}$ and $HO_2unicode{x22c5}$) and peroxides like hydrogen peroxide ($H_2O_2$), necessitating the presence of these defensive proteins.


Gluconeogenesis: How The Body Makes Glucose

If you’re on a low-carbohydrat e, ketogenic or carnivore diet (and even if you’re not), you’ve may have heard of the term gluconeogenesis. Since the word sounds similar to “glucose,” it may instill a sense of fear in carbo-phobes. We associate glucose with sugar. In fact, keto dieters sometimes fear that eating certain foods may even kick them out of ketosis due to the process of gluconeogenesis raising insulin.

Truth is, gluconeogenesis is harmless, and actually is a necessary process that allows us to create our own fuel to keep certain bodily processes going. Let’s take a deep dive into gluconeogenesis, looking at some of the science behind the term and the physiology behind the process.


Introduction

The primary role of red blood cells is the transport of respiratory gasses. In the lung, oxygen (O2) diffuses across the alveolar barrier from inspired air into blood, where the majority is bound by hemoglobin (Hb) to form oxy-Hb, a process called oxygenation. Hb is contained in the red blood cells, which, being circulated by the cardiovascular system, deliver O2 to the periphery where it is released from its Hb-bond (deoxygenation) and diffuses into the cells. While passing peripheral capillaries, carbon dioxide (CO2) produced by the cells reaches the red blood cells, where carbonic anhydrase (CA) in tissues and red blood cells converts a large portion of CO2 into bicarbonate (HCO − 3). CO2 is also bound by Hb, preferentially by deoxygenated Hb forming carboxy-bonds. Both forms of CO2 are delivered to the lung, where CA converts HCO − 3 back into CO2. CO2 is also released from its bond to Hb and diffuses across the alveolar wall to be expired.

The biological significance of O2 transport by Hb is well-illustrated by anemia where decreased Hb also decreases exercise performance despite a compensatory increase in cardiac output (Ledingham, 1977 Carroll, 2007), and by improved aerobic performance upon increasing total Hb (Berglund and Hemmingson, 1987). The O2 dissociation curves in Figure ​ Figure1 1 indicate the advantage of normal vs. anemic Hb showing that the O2 content in blood varies with the Hb concentration in blood at any given O2 partial pressure (PO2). Not only its amount but also the functional properties of Hb affect performance. This is illustrated by the observation that an increased Hb-O2 affinity favors O2 loading in the lung and survival in an hypoxic environment (Eaton et al., 1974 Hebbel et al., 1978), whereas a decreased Hb-O2 affinity favors the release of O2 from the Hb molecule in support of oxidative phosphorylation when the ATP demand is high, such as in exercising skeletal muscle (for a recent review see Mairbäurl and Weber, 2012).

Effects of hemoglobin concentration and pH, CO2, 2,3-DPG and temperature on blood oxygen content and on Hb-O2 affinity. Oxygen dissociation curves (ODC) were calculated with the equation by Severinghaus (1979) using decreased, normal, and increased P50 values. Oxygen content was calculated from SO2 and normal and decreased hemoglobin concentrations assuming that 1 g H binds 1.34 ml of O2. The insert indicates that an increase in pH, and a decrease in CO2, 2,3-DPG and temperature shifts the ODC to the left (red arrows and curves), whereas acidosis and increased CO2, 2,3-DPG and temperature shift the ODCs to the right.

Despite O2 transport, red blood cells fulfill a variety of other functions, all of which also may improve exercise performance. Likely the most important one is the contribution of red blood cells in buffering changes in blood pH by transport of CO2 and by binding of H + to hemoglobin. Red blood cells also take up metabolites such as lactate that is released from skeletal muscle cells during high intensity exercise. Uptake into red blood cells decreases the plasma concentration of metabolites. Finally, red blood cells seem to be able to decrease peripheral vascular resistance by releasing the vasodilator NO (Stamler et al., 1997) and by releasing ATP which stimulates endothelial NO formation causing arteriolar vasodilation and augments local blood flow (Gonzalez-Alonso et al., 2002).

This review summarizes the mechanisms by which red blood cells warrant O2 supply to the tissues with special emphasis on O2 transport to exercising muscle.


Introduction

T he main physiological role of red blood cells (RBCs), or erythrocytes is to transport of gases (O2, CO2) from the lung to the tissues and to maintain systemic acid/base equilibria. In addition, RBCs are well equipped with antioxidant systems, which essentially contribute to their function and integrity. Damage of red cell integrity, defined as hemolysis, has been shown to significantly contribute to severe pathologies, including endothelial dysfunction. Recent clinical and experimental evidence indicates that RBCs may be directly involved in tissue protection and regulation of cardiovascular homeostasis by exerting further noncanonical functions, including nitric oxide (NO) metabolism and control of blood rheology, as well as erythrocrine function (i.e., by releasing bioactive molecules, including NO, NO metabolites, and ATP). Many hypotheses on the role of noncanonical functions of RBCs in cardiovascular homeostasis have been put forward, and evidence of a central role played by RBCs in cardiovascular protection is accumulating. However, many aspects of RBC-mediated control of NO metabolism and ATP release are still speculative or not universally accepted.

Anemia is a pathological condition characterized by a decreased number of circulating RBCs and defined by hemoglobin (Hb) concentrations in whole blood below 12 g/dL in females and 13 g/dL in males (192). There is clinical evidence that anemia is also associated with a series of severe complications in cardiovascular disease (CVD) such as thromboembolic events (e.g., venous thrombosis and stroke). However, therapeutic interventions aimed to increase the circulating number of RBCs (e.g., by transfusion of blood or by administration of erythropoiesis-stimulating agents [ESAs] to stimulate the production of RBCs by the bone marrow), were not always effective in the tested cohorts (48, 91, 156). One possible explanation is that these treatments have side effects and therefore may contribute themselves to the negative outcome, for example, treatment with ESAs was associated with increased thromboembolic events (45).

Interpretation of large cohort studies may be very complex and requires recognition of many interacting features of disease and normal physiology. This is particularly true for studies evaluating the relationship between anemia and cardiovascular complications, which may involve different aspects, including changes in number or function of RBCs, in blood rheological properties, in systemic hemodynamics, and overall cardiovascular physiology and pathology.

In this article, we aim to provide a chemical, biophysical, and clinical perspective about the role of RBCs in the cardiovascular system, with focus on noncanonical functions of RBCs (Fig. 1). Specifically, we will describe (I) the role of redox regulation in RBCs to maintain cell functionality and integrity, including sources of reactive oxygen species (ROS), enzymatic and nonenzymatic antioxidant systems, and damage caused by dysregulation of the redox state (II) the complex role of RBCs in NO metabolism (III) the intrinsic mechanical properties of RBCs and their effects on blood rheology and hemodynamics (IV) the pathophysiology of specific anemic conditions, characterized by RBC dysfunction and hemolysis, and present mice models applied for basic and translational science studies and (V) the clinical aspects and therapeutic approaches for anemia in CVD, outlining the open questions and proposing possible research directions.

FIG. 1. RBC function and dysfunction: redox regulation, NO metabolism, and anemia. (A) Intrinsic RBC properties and function. Beside their canonical role in transport of gases and nutrients, RBCs are well equipped with redox buffer systems and are important modulators of NO metabolism. Their intrinsic mechanical properties allow them to deform/change their shape in response to changes in flow and to changes in vessel diameter, thus participating in control of blood rheology. (B) Effects of RBCs in blood. A second way for RBCs to control blood rheology is via their concentration (hematocrit), which critically defines blood viscosity and blood rheology. In addition, RBCs interact with PLTs resulting in a complex cell–cell communication involving membrane adhesion molecules, NO metabolism, and redox regulation. (C) Effects on systemic hemodynamics. In addition to control of vascular tone and cardiac function, intrinsic RBC properties and overall blood rheology are contributors to systemic vascular hemodynamics. (D) Anemia. RBC dysfunction mainly results in a number of anemic conditions, which are characterized by a decrease in blood Hb concentration and circulating number of RBCs. Redox dysregulation results mainly in hemolytic anemia and release of Hb, affecting redox metabolism and NO scavenging. Anemia affects systemic hemodynamics and myocardial performance. Furthermore, patients with CVD show disturbances in hemostasis and thromboembolism and increased mortality, which cannot be effectively treated by blood transfusion or substitution of ESAs. CVD, cardiovascular disease ESA, erythropoiesis-stimulating agent Hb, hemoglobin NO, nitric oxide PLT, platelet RBC, red blood cell. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars


Chronic Infections

Infections are invasions by pathogens, such as viruses, bacteria, fungi, and parasites that lead to damage in the body. Acute infections are usually fought off by your immune system and resolve within a relatively short period of time. For example, with proper treatment you can recover from an ear infection, respiratory infection or infected wound within a week or a few weeks. However, chronic infections are not resolved by your immune system and stick around for several months, even years, causing a variety of health problems.

The most common chronic viral infections include the Epstein-Barr virus, hepatitis, and herpes. The most common bacterial infections include bladder and urinary tract infections. In the past, some chronic bacterial infections led to dangerous epidemics, including the plague. The most common form of chronic fungal infections includes Candida overgrowth.

Chronic infections can lead to oxidative stress, chronic infections, and a compromised immune system. They have been linked to mitochondrial problems, chronic health issues, and disease, including digestive troubles and autoimmune disorders (9, 10, 11, 12) .


Glucose Metabolism

Glucose is the body's fuel. Without glucose, or without being able to convert it into energy rapidly and efficiently, we cannot survive in good health. So it's very important that our energy-metabolism system works efficiently. Here is a very simple explanation of how we convert glucose into energy.

  • In response to the rise in blood-glucose levels (say) after a meal, the pancreas releases insulin which "mops up" the glucose and carries it to cells that need extra energy.
  • The glucose enters the cell by special molecules in the membrane called “glucose transporters”.
  • The cells that need glucose have specific insulin receptors on their surface so that insulin can bind to them, encouraging glucose entry and utilization in the cells.
  • Once inside your cells, the glucose is burned to produce heat and adenosine triphosyphate, (ATP) a molecule that stores and releases energy as required by the cell.
  • The metabolism of glucose into energy may occur either in combination with oxygen (aerobic metabolism) or without it (anaerobic metabolism). The oxygen used comes from the mitochondria - tiny bodies inside the cell. However, red blood cells do not have mitochondria, so they change glucose into energy without the use of oxygen.
  • Glucose is also converted to energy in muscle cells - who are probably the most important energy "customers". These muscle cells do contain mitochondria so they can process glucose with oxygen. But even if oxygen-levels in the muscle-cell mitochondria fall too low, the cells can proceed to convert glucose into energy without oxygen. Unfortunately, turning glucose into energy without oxygen produces the by-product lactic acid. And too much lactic acid makes your muscles ache

Why don't red blood cells have DNA?

Diana - Yes, it is, exactly. Mature red blood cells have no nucleus which is the compartment that houses the DNA. Immature red blood cells actually do have a nucleus but when they differentiate to become the mature red blood cells the nucleus is actually ejected, so they have no nucleus and no DNA.

As to why this is and how they function, I think the answer is really lies in what they do. Red blood cells, their only real job is to carry oxygen around the body. Not having a nucleus is actually useful for this in terms of they can have more space for hemoglobin, which is the protein which carries oxygen. And also the red blood cells need to be able to squeeze through narrow capillaries, and they have this biconcave disc shape and without a nucleus this is possible.

Chris - This sort of figure eight shape? When you look at them side on they look like a sort of number eight turned on its side don’t they?


Centrioles

Centrioles are organelles involved in cell division. The function of centrioles is to help organize the chromosomes before cell division occurs so that each daughter cell has the correct number of chromosomes after the cell divides. Centrioles are found only in animal cells and are located near the nucleus. Each centriole is made mainly of a protein named tubulin. The centriole is cylindrical in shape and consists of many microtubules, as shown in the model pictured below.

Figure (PageIndex<6>): Centrioles are tiny cylinders near the nucleus, enlarged here to show their tubular structure.


Carbohydrate Metabolism

It should be noted that glucose 6-phosphate from glycogen does not require the hexokinase reaction. In skeletal muscle, glucose 6-phosphate from glycogen breakdown is a major substrate for glycolysis.

In this reaction, there is an intramolecular shift of a hydrogen atom, changing the location of the double bond. Phosphoglucose isomerase functions close to equilibrium, and therefore the reaction is reversible under intracellular conditions.

Glyceraldehyde 3-phosphate is in the direct path of glycolysis, but dihydroxyacetone phosphate is not. Dihydroxyacetone phosphate is isomerized to glyceraldehyde 3-phosphate via the action of triose-phosphate isomerase. The net result of the aldolase and triose-phosphate isomerase reactions is the production of two molecules of glyceraldehyde 3-phosphate. The series of reactions that converts one molecule of glucose to two molecules of glyceraldehyde 3-phosphate constitutes the first phase of glycolysis in which the chemical energy of ATP is used to generate phosphorylated intermediates. The dihydroxyacetone phosphate produced by the aldolase reaction may also be reduced to glycerol 3-phosphate and used for synthesis of glycerolipids this is a particularly important source of glycerol 3-phosphate for triacylglycerol synthesis in small intestinal enterocytes and in adipocytes.

This reaction incorporates inorganic phosphate (P i ) to produce a high-energy phosphate bond in 1,3-bisphosphoglycerate. The second product of the reaction, NADH, provides reducing equivalents for the energy conversion of electron transport and production of ATP by oxidative phosphorylation. This is the only glycolytic reaction that generates reducing equivalents for electron transport. It is important to note that the coenzyme NAD + is present in limited amounts in the cytosol. For this reason, the NAD + used in the glyceraldehyde 3-phosphate reaction needs to be regenerated in the cytosolic compartment so that NAD + availability does not limit glycolysis.

The enzyme that catalyzes this reaction is phosphoglycerate kinase. This is the first reaction in glycolysis that generates ATP. The formation of ATP by transfer of the phosphate group from 1,3-bisphosphoglycerate to ADP is a substrate-level phosphorylation.


Further Reading

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