Cellular respiration

Cellular respiration is the process of oxidizing biological fuels using an inorganic electron acceptor, such as oxygen, to drive production of adenosine triphosphate, which stores chemical energy in a biologically accessible form. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells to transfer chemical energy from nutrients to ATP, with the flow of electrons to an electron acceptor, and then release waste products.
If the electron acceptor is oxygen, the process is more specifically known as aerobic cellular respiration. If the electron acceptor is a molecule other than oxygen, this is anaerobic cellular respiration – not to be confused with fermentation, which is also an anaerobic process, but it is not respiration, as no external electron acceptor is involved.
The reactions involved in respiration are catabolic reactions, which break large molecules into smaller ones, producing ATP. Respiration is one of the key ways a cell releases chemical energy to fuel cellular activity. The overall reaction occurs in a series of biochemical steps, some of which are redox reactions. Although cellular respiration is technically a combustion reaction, it is an unusual one because of the slow, controlled release of energy from the series of reactions.
Nutrients that are commonly used by animal and plant cells in respiration include sugar, amino acids and fatty acids, and the most common oxidizing agent is molecular oxygen. The chemical energy stored in ATP can then be used to drive processes requiring energy, including biosynthesis, locomotion, or transportation of molecules across cell membranes.

Aerobic respiration

Aerobic respiration requires oxygen in order to create ATP. Although carbohydrates, fats, and proteins are consumed as reactants, aerobic respiration is the preferred method of pyruvate production in glycolysis, and requires pyruvate be transported by the mitochondria in order to be oxidized by the citric acid cycle. The products of this process are carbon dioxide and water, and the energy transferred is used to make bonds between ADP and a third phosphate group to form ATP, by substrate-level phosphorylation, NADH and FADH₂.
The negative ΔG indicates that the reaction is exothermic and can occur spontaneously.
The potential of NADH and FADH₂ is converted to more ATP through an electron transport chain with oxygen and protons as the "terminal electron acceptors". Most of the ATP produced by aerobic cellular respiration is made by oxidative phosphorylation. The energy released is used to create a chemiosmotic potential by pumping protons across a membrane. This potential is then used to drive ATP synthase and produce ATP from ADP and a phosphate group. Biology textbooks often state that 38 ATP molecules can be made per oxidized glucose molecule during cellular respiration. However, this maximum yield is never quite reached because of losses due to leaky membranes as well as the cost of moving pyruvate and ADP into the mitochondrial matrix, and current estimates range around 29 to 30 ATP per glucose.
Aerobic metabolism is up to 15 times more efficient than anaerobic metabolism. However, some anaerobic organisms, such as methanogens are able to continue with anaerobic respiration, yielding more ATP by using inorganic molecules other than oxygen as final electron acceptors in the electron transport chain. They share the initial pathway of glycolysis but aerobic metabolism continues with the Krebs cycle and oxidative phosphorylation. The post-glycolytic reactions take place in the mitochondria in eukaryotic cells, and in the cytoplasm in prokaryotic cells.
Although plants are net consumers of carbon dioxide and producers of oxygen via photosynthesis, plant respiration accounts for about half of the CO₂ generated annually by terrestrial ecosystems.

Glycolysis

is a metabolic pathway that takes place in the cytosol of cells in all living organisms. Glycolysis can be literally translated as "sugar splitting", and occurs regardless of oxygen's presence or absence. The process converts one molecule of glucose into two molecules of pyruvate, generating energy in the form of two net molecules of ATP. Four molecules of ATP per glucose are actually produced, but two are consumed as part of the preparatory phase. The initial phosphorylation of glucose is required to increase the reactivity in order for the molecule to be cleaved into two pyruvate molecules by the enzyme aldolase. During the pay-off phase of glycolysis, four phosphate groups are transferred to four ADP by substrate-level phosphorylation to make four ATP, and two NADH are also produced during the pay-off phase. The overall reaction can be expressed this way:
Starting with glucose, 1 ATP is used to donate a phosphate to glucose to produce glucose 6-phosphate. Glycogen can be converted into glucose 6-phosphate as well with the help of glycogen phosphorylase. During energy metabolism, glucose 6-phosphate becomes fructose 6-phosphate. An additional ATP is used to phosphorylate fructose 6-phosphate into fructose 1,6-bisphosphate by the help of phosphofructokinase. Fructose 1,6-biphosphate then splits into two phosphorylated molecules with three carbon chains which later degrades into pyruvate.

Oxidative decarboxylation of pyruvate

Pyruvate is oxidized to acetyl-CoA and CO₂ by the pyruvate dehydrogenase complex. The PDC contains multiple copies of three enzymes and is located in the mitochondria of eukaryotic cells and in the cytosol of prokaryotes. In the conversion of pyruvate to acetyl-CoA, one molecule of NADH and one molecule of CO₂ is formed.

Citric acid cycle

The citric acid cycle is also called the Krebs cycle or the tricarboxylic acid cycle. When oxygen is present, acetyl-CoA is produced from the pyruvate molecules created from glycolysis. Once acetyl-CoA is formed, aerobic or anaerobic respiration can occur. When oxygen is present, the mitochondria will undergo aerobic respiration which leads to the Krebs cycle. However, if oxygen is not present, fermentation of the pyruvate molecule will occur. In the presence of oxygen, when acetyl-CoA is produced, the molecule then enters the citric acid cycle inside the mitochondrial matrix, and is oxidized to CO₂ while at the same time reducing NAD to NADH. NADH can be used by the electron transport chain to create further ATP as part of oxidative phosphorylation. To fully oxidize the equivalent of one glucose molecule, two acetyl-CoA must be metabolized by the Krebs cycle. Two low-energy waste products, H₂O and CO₂, are created during this cycle.
The citric acid cycle is an 8-step process involving 18 different enzymes and co-enzymes. During the cycle, acetyl-CoA + oxaloacetate yields citrate, which is rearranged to a more reactive form called isocitrate. Isocitrate is modified to become α-ketoglutarate, succinyl-CoA, succinate, fumarate, malate and, finally, oxaloacetate.
The net gain from one cycle is 3 NADH and 1 FADH₂ as hydrogen carrying compounds and 1 high-energy GTP, which may subsequently be used to produce ATP. Thus, the total yield from 1 glucose molecule is 6 NADH, 2 FADH₂, and 2 ATP.

Oxidative phosphorylation

In eukaryotes, oxidative phosphorylation occurs in the mitochondrial cristae. It comprises the electron transport chain that establishes a proton gradient across the boundary of the inner membrane by oxidizing the NADH produced from the Krebs cycle. ATP is synthesized by the ATP synthase enzyme when the chemiosmotic gradient is used to drive the phosphorylation of ADP. The electrons are finally transferred to exogenous oxygen and, with the addition of two protons, water is formed.

Efficiency of ATP production

The table below describes the reactions involved when one glucose molecule is fully oxidized into carbon dioxide. It is assumed that all the reduced coenzymes are oxidized by the electron transport chain and used for oxidative phosphorylation.
Although there is a theoretical yield of 38 ATP molecules per glucose during cellular respiration, such conditions are generally not realized because of losses such as the cost of moving pyruvate, phosphate, and ADP into the mitochondria. All are actively transported using carriers that utilize the stored energy in the proton electrochemical gradient.

Pyruvate is taken up by a specific, low K_m transporter to bring it into the mitochondrial matrix for oxidation by the pyruvate dehydrogenase complex.
The phosphate carrier mediates the electroneutral exchange of phosphate for OH⁻ or symport of phosphate and protons across the inner membrane, and the driving force for moving phosphate ions into the mitochondria is the proton motive force.
The ATP-ADP translocase is an antiporter and exchanges ADP and ATP across the inner membrane. The driving force is due to the ATP having a more negative charge than the ADP, and thus it dissipates some of the electrical component of the proton electrochemical gradient.

The outcome of these transport processes using the proton electrochemical gradient is that more than 3 H⁺ are needed to make 1 ATP. Obviously, this reduces the theoretical efficiency of the whole process and the likely maximum is closer to 28–30 ATP molecules. In practice the efficiency may be even lower because the inner membrane of the mitochondria is slightly leaky to protons. Other factors may also dissipate the proton gradient creating an apparently leaky mitochondria. An uncoupling protein known as thermogenin is expressed in some cell types and is a channel that can transport protons. When this protein is active in the inner membrane it short circuits the coupling between the electron transport chain and ATP synthesis. The potential energy from the proton gradient is not used to make ATP but generates heat. This is particularly important in brown fat thermogenesis of newborn and hibernating mammals.
File:Cellular respiration.gif|thumb|Stoichiometry of aerobic respiration and most known fermentation types in eucaryotic cell. Numbers in circles indicate counts of carbon atoms in molecules, C6 is glucose C₆H₁₂O₆, C1 carbon dioxide CO₂. Mitochondrial outer membrane is omitted.
According to some newer sources, the ATP yield during aerobic respiration is not 36–38, but only about 30–32 ATP molecules / 1 molecule of glucose, because:

ATP : NADH+H⁺ and ATP : FADH₂ ratios during the oxidative phosphorylation appear to be not 3 and 2, but 2.5 and 1.5 respectively. Unlike in the substrate-level phosphorylation, the stoichiometry here is difficult to establish.
* ATP synthase produces 1 ATP / 3 H⁺. However the exchange of matrix ATP for cytosolic ADP and Pi mediated by ATP–ADP translocase and phosphate carrier consumes 1 H⁺ / 1 ATP as a result of regeneration of the transmembrane potential changed during this transfer, so the net ratio is 1 ATP : 4 H⁺.
* The mitochondrial electron transport chain proton pump transfers across the inner membrane 10 H⁺ / 1 NADH+H⁺ or 6 H⁺ / 1 FADH₂.
ATP : NADH+H⁺ coming from glycolysis ratio during the oxidative phosphorylation is
* 1.5, as for FADH₂, if hydrogen atoms are transferred from cytosolic NADH+H⁺ to mitochondrial FAD by the glycerol phosphate shuttle located in the inner mitochondrial membrane.
* 2.5 in case of malate-aspartate shuttle transferring hydrogen atoms from cytosolic NADH+H⁺ to mitochondrial NAD⁺

So finally we have, per molecule of glucose

Substrate-level phosphorylation: 2 ATP from glycolysis + 2 ATP from Krebs cycle
Oxidative phosphorylation
* 2 NADH+H⁺ from glycolysis: 2 × 1.5 ATP or 2 × 2.5 ATP
* 2 NADH+H⁺ from the oxidative decarboxylation of pyruvate and 6 from Krebs cycle: 8 × 2.5 ATP
* 2 FADH₂ from the Krebs cycle: 2 × 1.5 ATP

Altogether this gives 4 + 3 + 20 + 3 = 30 ATP per molecule of glucose
These figures may still require further tweaking as new structural details become available. The above value of 3 H⁺ / ATP for the synthase assumes that the synthase translocates 9 protons, and produces 3 ATP, per rotation. The number of protons depends on the number of c subunits in the Fo c-ring, and it is now known that this is 10 in yeast Fo and 8 for vertebrates. Including one H⁺ for the transport reactions, this means that synthesis of one ATP requires protons in yeast and in vertebrates. This would imply that in human mitochondria the 10 protons from oxidizing NADH would produce 2.72 ATP and the 6 protons from oxidizing succinate or ubiquinol would produce 1.64 ATP. This is consistent with experimental results within the margin of error described in a recent review.
The total ATP yield in ethanol or lactic acid fermentation is only 2 molecules coming from glycolysis, because pyruvate is not transferred to the mitochondrion and finally oxidized to the carbon dioxide, but reduced to ethanol or lactic acid in the cytoplasm.