Editing Cellular respiration (section)

==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 [[reduction (chemistry)|reduced]] [[coenzyme]]s are oxidized by the electron transport chain and used for oxidative phosphorylation.
{| class="wikitable"
|-
!Step
!coenzyme yield
!ATP yield
!Source of ATP
|-
| style="border-top:solid 3px #aaa;"|Glycolysis preparatory phase
| style="border-top:solid 3px #aaa;"|
| style="border-top:solid 3px #aaa; text-align:center;"| −2
| style="border-top:solid 3px #aaa;"|Phosphorylation of glucose and fructose 6-phosphate uses two ATP from the cytoplasm.
|-
|rowspan="2"|Glycolysis pay-off phase
|
| style="text-align:center;"|4
|Substrate-level phosphorylation
|-
| style="text-align:center;"|2 NADH
| style="text-align:center;"|3 or 5
|Oxidative phosphorylation: Each NADH produces net 1.5 ATP (instead of usual 2.5) due to NADH transport over the mitochondrial membrane
|-
|Oxidative decarboxylation of pyruvate
| style="text-align:center;"| 2 NADH
| style="text-align:center;"| 5
|Oxidative phosphorylation
|-
|rowspan="3"|Krebs cycle
|
| style="text-align:center;"|2
|Substrate-level phosphorylation
|-
| style="text-align:center;"|6 NADH
| style="text-align:center;"|15
| Oxidative phosphorylation
|-
| style="text-align:center;"|2 FADH<sub>2</sub>
| style="text-align:center;"|3
| Oxidative phosphorylation
|-
| colspan="2" style="border-top:solid 3px #aaa; text-align:center;"|'''Total yield'''
| style="border-top:solid 3px #aaa; text-align:center;"|'''30 or 32 ATP'''
| style="border-top:solid 3px #aaa;"|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 38 ATP molecules per glucose during cellular respiration, such conditions are generally not realized because of 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 utilize the stored energy in the proton [[electrochemical gradient]].{{cn|date=May 2025}}
* Pyruvate is taken up by a specific, low ''K''<sub>m</sub> transporter to bring it into the mitochondrial matrix for oxidation by the pyruvate dehydrogenase complex.
* The '''[[SLC25A3|phosphate carrier]]''' (PiC) mediates the electroneutral exchange ([[Antiporter|antiport]]) of phosphate ({{chem2|H2PO4-}}; P<sub>i</sub>) for OH<sup>−</sup> or [[Symporter|symport]] of phosphate and protons (H<sup>+</sup>) across the inner membrane, and the driving force for moving phosphate ions into the mitochondria is the [[Chemiosmosis#Proton-motive force|proton motive force]].
* The '''[[ATP-ADP translocase]]''' (also called [[Adenine nucleotide translocator|adenine nucleotide translocase, ANT]]) is an [[antiporter]] and exchanges ADP and ATP across the [[Inner nuclear membrane|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<sup>+</sup> 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.<ref name=Rich/> In practice the efficiency may be even lower because the inner membrane of the mitochondria is slightly leaky to protons.<ref>{{Cite journal
| pmid = 7654171
| date = 1 September 1995
| title = Mitochondrial proton conductance and H<sup>+</sup>/O ratio are independent of electron transport rate in isolated hepatocytes
| volume = 310 | first2 = M.
| issue =  Pt 2
| last2 = Brand
| last1 = Porter
| pages = 379–382
| issn = 0264-6021
| pmc = 1135905 | first1 = R.
| journal = The Biochemical Journal
| type = Free full text
 | doi=10.1042/bj3100379}}</ref> 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 synthase|ATP synthesis]]. The potential energy from the proton gradient is not used to make ATP but generates heat. This is particularly important in [[Brown adipose tissue|brown fat]] thermogenesis of newborn and hibernating mammals.{{cn|date=May 2025}}

[[File:Cellular respiration.gif|thumb|[[Stoichiometry]] of [[aerobic respiration]] and most known [[Fermentation (biochemistry)|fermentation]] types in [[Eucaryota|eucaryotic]] cell. {{r|Stryer95}} Numbers in circles indicate counts of carbon atoms in molecules, C6 is [[glucose]] C<sub>6</sub>H<sub>12</sub>O<sub>6</sub>, C1 [[carbon dioxide]] CO<sub>2</sub>. [[Mitochondrion|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 {{r|Stryer95}}, because:
* ATP : NADH+H<sup>+</sup> and ATP : FADH<sub>2</sub> 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<sup>+</sup>. However the exchange of matrix ATP for cytosolic ADP and Pi (antiport with OH<sup>−</sup> or symport with H<sup>+</sup>) mediated by [[ATP–ADP translocase]] and [[SLC25A3|phosphate carrier]] consumes 1 H<sup>+</sup> / 1 ATP as a result of regeneration of the transmembrane potential changed during this transfer, so the net ratio is 1 ATP : 4 H<sup>+</sup>.
** The mitochondrial [[electron transport chain]] [[proton pump]] transfers across the inner membrane 10 H<sup>+</sup> / 1 NADH+H<sup>+</sup> (4 + 2 + 4) or 6 H<sup>+</sup> / 1 FADH<sub>2</sub> (2 + 4).
:So the final stoichiometry is
:1 NADH+H<sup>+</sup> : 10 H<sup>+</sup> : 10/4 ATP = 1 NADH+H<sup>+</sup> : 2.5 ATP
:1 FADH<sub>2</sub> : 6 H<sup>+</sup> : 6/4 ATP = 1 FADH<sub>2</sub> : 1.5 ATP
* ATP : NADH+H<sup>+</sup> coming from glycolysis ratio during the oxidative phosphorylation is
** 1.5, as for FADH<sub>2</sub>, if hydrogen atoms (2H<sup>+</sup>+2e<sup>−</sup>) are transferred from cytosolic NADH+H<sup>+</sup> 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<sup>+</sup> to mitochondrial NAD<sup>+</sup>

So finally we have, per molecule of glucose
* [[Substrate-level phosphorylation]]: 2 ATP from [[glycolysis]] + 2 ATP (directly GTP) from [[Krebs cycle]]
* [[Oxidative phosphorylation]]
** 2 NADH+H<sup>+</sup> from glycolysis: 2 × 1.5 ATP (if glycerol phosphate shuttle transfers hydrogen atoms) or 2 × 2.5 ATP (malate-aspartate shuttle)
** 2 NADH+H<sup>+</sup> from the [[Pyruvate decarboxylation|oxidative decarboxylation of pyruvate]] and 6 from Krebs cycle: 8 × 2.5 ATP
** 2 FADH<sub>2</sub> from the Krebs cycle: 2 × 1.5 ATP
Altogether this gives 4 + 3 (or 5) + 20 + 3 = 30 (or 32) ATP per molecule of glucose

These figures may still require further tweaking as new structural details become available. The above value of 3 H<sup>+</sup> / 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 [[ATP synthase#FO region|Fo c-ring]], and it is now known that this is 10 in yeast Fo<ref>{{cite journal |title=Molecular architecture of the rotary motor in ATP synthase |journal=Science| volume = 286| pages = 1700–5 | year = 1999|issue= 5445| pmid =10576729| doi=10.1126/science.286.5445.1700|last1=Stock |first1=Daniela |last2=Leslie |first2=Andrew G. W. |last3=Walker |first3=John E. }}</ref> and 8 for vertebrates.<ref>{{cite journal |title=Bioenergetic Cost of Making an Adenosine Triphosphate Molecule in Animal Mitochondria |journal=Proc. Natl. Acad. Sci. USA| volume = 107| pages = 16823–16827 | year = 2010|issue=39 | pmid = 20847295 | doi=10.1073/pnas.1011099107 | pmc=2947889|doi-access=free |last1=Watt |first1=Ian N. |last2=Montgomery |first2=Martin G. |last3=Runswick |first3=Michael J. |last4=Leslie |first4=Andrew G. W. |last5=Walker |first5=John E. }}</ref> Including one H<sup>+</sup> for the transport reactions, this means that synthesis of one ATP requires {{nowrap|1 + 10/3 {{=}} 4.33}} protons in [[yeast]] and {{nowrap|1 + 8/3 {{=}} 3.67}} in [[vertebrate]]s. This would imply that in human mitochondria the 10 protons from oxidizing NADH would produce 2.72 ATP (instead of 2.5) and the 6 protons from oxidizing succinate or ubiquinol would produce 1.64 ATP (instead of 1.5). This is consistent with experimental results within the margin of error described in a recent review.<ref>{{cite journal |title= P/O ratios of mitochondrial oxidative phosphorylation|author =P.Hinkle|journal =Biochimica et Biophysica Acta (BBA) - Bioenergetics| volume = 1706| pages = 1–11 | year = 2005|issue =1–2| pmid = 15620362| doi=10.1016/j.bbabio.2004.09.004| doi-access = }}</ref>

The total ATP yield in ethanol or lactic acid [[Fermentation (biochemistry)|fermentation]] is only 2 molecules coming from [[glycolysis]], because pyruvate is not transferred to the [[mitochondrion]] and finally oxidized to the carbon dioxide (CO<sub>2</sub>), but reduced to [[Ethanol fermentation|ethanol]] or [[Lactic acid fermentation|lactic acid]] in the [[cytoplasm]].<ref name="Stryer95">{{cite book |last=Stryer |first=Lubert |year=1995 |title=Biochemistry |publisher=W. H. Freeman and Company |location=New York – Basingstoke |edition=fourth |isbn=978-0716720096 }}</ref>