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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?

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    $\begingroup$ What exactly do you mean by "metabolize glucose"? Glucose is mostly converted to lactate in red blood cells, but some is oxidized to CO2 by the pentose phosphate pathway. Are you askiing about metabolism to CO2? $\endgroup$
    – Roland
    May 31, 2015 at 6:33
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    $\begingroup$ I mean metabolism to atp and co2. $\endgroup$
    – Caters
    May 31, 2015 at 7:35

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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.

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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 $HO_2\unicode{x22c5}$) and peroxides like hydrogen peroxide ($H_2O_2$), necessitating the presence of these defensive proteins.

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    $\begingroup$ where do you get your numbers from? I've never seen any cell metabolize 90% of its glucose through the penthose phophate pathway. Typical numbers are more like 10--30% of hexokinase flux diverted through the PPP, and the remainder through upper glycolysis (see for example sciencedirect.com/science/article/pii/S0165022X99000056). In terms of carbon, this corresponds to 2--5% evolved as CO2, and the remainder metabolized to lactate. $\endgroup$
    – Roland
    May 31, 2015 at 6:31
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    $\begingroup$ I thought most of the anaerobic metabolism comes from glycolysis and lactic acid fermentation(which unless you are talking about fructose eventually turning into glucose or DNA or RNA does not involve the pentose phosphate pathway). $\endgroup$
    – Caters
    May 31, 2015 at 7:41
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    $\begingroup$ @MattDMo, also NADH and ATP is not produced by the pentose phosphate pathway, but NADPH is. On the other the "anaerobic pathway" (I assume you mean glycolysis?) does not produce NADPH, but does produce NADH and ATP. It seems like you have mixed up the names of the pathways? $\endgroup$
    – Roland
    May 31, 2015 at 8:30
  • $\begingroup$ @Caters, glycolysis and the PPP are interconnected, but yes, most glucose carbon in red cells is processed "straight" through glycolysis and converted to lactate. The PPP can operate to yield NADPH without producing ribose for RNA/DNA though. I posted an answer to clarify the details. $\endgroup$
    – Roland
    May 31, 2015 at 10:51
  • $\begingroup$ @Roland I apologize for not including all my sources - while a lot was found in the links I gave, I also based some of the answer on this page from the Children’s Hospital & Research Center Oakland. $\endgroup$
    – MattDMo
    May 31, 2015 at 15:59

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