Editor-In-Chief: C. Michael Gibson, M.S., M.D. 
Cellular respiration describes the metabolic reactions and processes that take place in a cell or across the cell membrane to obtain biochemical energy from fuel molecules and the release of the cells' waste products. Energy is released by the oxidation of fuel molecules and is stored as "high-energy" carriers. The reactions involved in respiration are catabolic reactions in metabolism.
Fuel molecules commonly used by cells in respiration include glucose, amino acids and fatty acids, and a common oxidizing agent (electron acceptor) is molecular oxygen (O2). There are organisms, however, that can respire using other organic molecules as electron acceptors instead of oxygen. Organisms that use oxygen as a final electron acceptor in respiration are described as aerobic, while those that do not are referred to as anaerobic.
The energy released in respiration is used to synthesize molecules that act as a chemical storage of this energy. One of the most widely used compounds in a cell is adenosine triphosphate (ATP) and its stored chemical energy can be used for many processes requiring energy, including biosynthesis, locomotion or transportation of molecules across cell membranes. Because of its ubiquitous nature, ATP is also known as the "universal energy currency", since the amount of it in a cell indicates how much energy is available for energy-consuming processes.
Aerobic respiration requires oxygen in order to generate energy (ATP). It is the preferred method of pyruvate breakdown from glycolysis and requires that pyruvate enter the mitochondrion to be fully oxidized by the Krebs cycle. The product of this process is energy in the form of ATP (Adenosine Triphosphate), by substrate-level phosphorylation, NADH and FADH2.
Simplified Reaction: C6H12O6 (aq) + 6O2 (g) → 6CO2 (g) + 6H2O (l) ΔHc -2880 kJ
The reducing potential of NADH and FADH2 is converted to more ATP through an electron transport chain with oxygen as the "terminal electron acceptor". Most of the ATP produced by aerobic cellular respiration is made by oxidative phosphorylation. This works by the energy released in the consumption of pyruvate being 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. Biology textbooks often state that between 36-38 ATP molecules can be made per oxidised glucose molecule during cellular respiration (2 from glycolysis, 2 from the Krebs cycle, and about 32-34 from the electron transport system). Generally, 38 ATP molecules are formed from aerobic respiration. However, this maximum yield is never quite reached due to losses (leaky membranes) as well as the cost of moving pyruvate and ADP into the mitochondrial matrix.
Aerobic metabolism is 19 times more efficient than anaerobic metabolism (which yields 2 mol ATP per 1 mol glucose). 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.
Glycolysis is a metabolic pathway that is found in the cytoplasm of cells in all living organisms and does not require oxygen. The process converts one molecule of glucose into two molecules of pyruvate, and makes energy in the form of two net molecules of ATP. Four molecules of ATP per glucose are actually produced; however, two are consumed for the preparatory phase. The initial phosphorylation of glucose is required to destabilize the molecule for cleavage into two triose sugars. During the pay-off phase of glycolysis, four phosphate groups are transferred to ADP by substrate-level phosphorylation to make four ATP, and two NADH are produced when the triose sugars are oxidized. Glycolysis takes place in the cytoplasm of the cell. The overall reaction can be expressed this way:
- Glucose + 2 NAD+ + 2 Pi + 2 ADP → 2 pyruvate + 2 NADH + 2 ATP + 2 H2O
Oxidative decarboxylation of pyruvate
The pyruvate produced in glycolysis is transported across the mitochondrial membranes by a membrane transport protein called the pyruvate carrier. The pyruvate decarboxylase then produces acetyl-CoA from pyruvate inside the mitochondrial matrix. This oxidation reaction also releases carbon dioxide as a product. In the process one molecule of NADH is formed per pyruvate oxidized.
Citric Acid cycle
This is also called the Krebs cycle or also the tricarboxylic acid cycle. When oxygen is present, acetyl-CoA is produced from pyruvate. If oxygen is not present the cell undergoes fermentation of the pyruvate molecule. If acetyl-CoA is produced the molecule then enters the citric acid cycle (Krebs cycle) inside the mitochondrial matrix, and gets 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 waste products, H2O and CO2, are created during this cycle.
In eukaryotes, oxidative phosphorylation occurs in the mitochondrial cristae. It comprises the electron transport chain that establishes a proton gradient (chemiosmotic potential) across the inner membrane by oxidizing the NADH produced from the Krebs cycle. ATP is synthesised by the ATP synthase enzyme when the chemiosmotic gradient is used to drive the phosphorylation of ADP.
The yields in the table below are for one glucose molecule being 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.
|Step||coenzyme yield||ATP yield||Source of ATP|
|Glycolysis preparatory phase||-2||Phosphorylation of glucose and fructose 6-phosphate uses two ATP from the cytoplasm.|
|Glycolysis pay-off phase||4||Substrate-level phosphorylation|
|2 NADH||4 (6)||Oxidative phosphorylation. Only 2 ATP per NADH since the coenzyme must feed into the electron transport chain from the cytoplasm rather than the mitochondrial matrix. If the malate shuttle is used to move NADH into the mitochondria this might count as 3 ATP per NADH.|
|Oxidative decarboxylation||2 NADH||6||Oxidative phosphorylation|
|Krebs cycle||2||Substrate-level phosphorylation|
|6 NADH||18||Oxidative phosphorylation|
|2 FADH2||4||Oxidative phosphorylation|
|Total yield||36 (38) ATP||From the complete oxidation of one glucose molecule to carbon dioxide and oxidation of all the reduced coenzymes.|
Although there is a theoretical yield of 36-38 ATP molecules per glucose during cellular respiration, such conditions are generally not realized due to losses such as the cost of moving pyruvate (from glycolysis), phosphate, and ADP (substrates for ATP synthesis) into the mitochondria. All are actively transported using carriers that utilise the stored energy in the proton electrochemical gradient.
- The pyruvate carrier is a symporter and the driving force for moving pyruvate into the mitochondria is the movement of protons from the intermembrane space to the matrix.
- The phosphate carrier is an antiporter and the driving force for moving phosphate ions into the mitochondria is the movement of hydroxyls ions from the matrix to the intermembrane space.
- The adenine nucleotide carrier is an antiporter and exchanges ADP and ATP across the inner membrane. The driving force is due to the ATP (-4) having a more negative charge than the ADP (-3) 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 due to the inner membrane of the mitochondria being 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 a baby's brown fat, for thermogenesis, and hibernating animals.
- Main article: Anaerobic respiration
Without oxygen, pyruvate is not metabolized by cellular respiration but undergoes a process of fermentation. The pyruvate is not transported into the mitochondrion, but remains in the cytoplasm, where it is converted to waste products that may be removed from the cell. This serves the purpose of oxidizing the hydrogen carriers so that they can perform glycolysis again and removing the excess pyruvate. This waste product varies depending on the organism. In skeletal muscles, the waste product is lactic acid. This type of fermentation is called lactic acid fermentation. In yeast, the waste products are ethanol and carbon dioxide. This type of fermentation is known as alcoholic or ethanol fermentation. The ATP generated in this process is made by substrate phosphorylation, which is phosphorylation that does not involve oxygen.
Anaerobic respiration is less efficient at using the energy from glucose since 2 ATP are produced during anaerobic respiration per glucose, compared to the 30 ATP per glucose produced by aerobic respiration. This is because the waste products of anaerobic respiration still contain plenty of energy. Ethanol, for example, can be used in gasoline (petrol) solutions. Glycolytic ATP, however, is created more quickly. For prokaryotes to continue a rapid growth rate when they are shifted from an aerobic environment to an anaerobic environment, they must increase the rate of the glycolytic reactions. Thus, during short bursts of strenuous activity, muscle cells use anaerobic respiration to supplement the ATP production from the slower aerobic respiration, so anaerobic respiration may be used by a cell even before the oxygen levels are depleted, as is the case in sports that do not require athletes to pace themselves, such as sprinting.
- Tetrazolium chloride: cellular respiration indicator
- ↑ Sugden MC, Holness MJ (2003). "Trials, tribulations and finally, a transporter: the identification of the mitochondrial pyruvate transporter". Biochem. J. 374 (Pt 3): e1–2. PMID 12954079.
- ↑ Rich PR (2003). "The molecular machinery of Keilin's respiratory chain". Biochem. Soc. Trans. 31 (Pt 6): 1095–105. PMID 14641005.
- ↑ Porter RK, Brand MD (1995). "Mitochondrial proton conductance and H+/O ratio are independent of electron transport rate in isolated hepatocytes". Biochem. J. 310 ( Pt 2): 379–82. PMID 7654171.
- Chart of Important Metabolic Products
- A detailed description of respiration vs. fermentation
- Kimball's online resource to cellular respiration
- Cellular Respiration and Fermentation at Clermont College
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