Editing Mitochondrion (section)

===Energy conversion===
A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of [[glucose]]: [[pyruvate]], and [[NADH]], which are produced in the cytosol.<ref name="Voet-2006"/> This type of [[cellular respiration]], known as [[aerobic respiration]], is dependent on the presence of [[oxygen]]. When oxygen is limited, the glycolytic products will be metabolized by [[Fermentation (biochemistry)|anaerobic fermentation]], a process that is independent of the mitochondria.<ref name="Voet-2006"/> The production of ATP from glucose and oxygen has an approximately 13-times higher yield during aerobic respiration compared to fermentation.<ref>{{cite journal | vauthors = Rich PR | title = The molecular machinery of Keilin's respiratory chain | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 6 | pages = 1095–1105 | date = December 2003 | pmid = 14641005 | doi = 10.1042/BST0311095 }}</ref> Plant mitochondria can also produce a limited amount of ATP either by breaking the sugar produced during photosynthesis or without oxygen by using the alternate substrate [[nitrite]].<ref name="Stoimenova-2007">{{cite journal | vauthors = Stoimenova M, Igamberdiev AU, Gupta KJ, Hill RD | title = Nitrite-driven anaerobic ATP synthesis in barley and rice root mitochondria | journal = Planta | volume = 226 | issue = 2 | pages = 465–474 | date = July 2007 | pmid = 17333252 | doi = 10.1007/s00425-007-0496-0 | bibcode = 2007Plant.226..465S }}</ref> ATP crosses out through the inner membrane with the help of a [[ATP–ADP translocase|specific protein]], and across the outer membrane via [[Porin (protein)|porins]].<ref name="Neupert-1997">{{cite journal | vauthors = Neupert W | title = Protein import into mitochondria | journal = Annual Review of Biochemistry | volume = 66 | pages = 863–917 | year = 1997 | pmid = 9242927 | doi = 10.1146/annurev.biochem.66.1.863 }}</ref> After conversion of ATP to [[Adenosine diphosphate|ADP]] by [[dephosphorylation]] that releases energy, ADP returns via the same route.

====Pyruvate and the citric acid cycle====
{{Main|Citric acid cycle}}

[[Pyruvate]] molecules produced by [[glycolysis]] are [[active transport|actively transported]] across the inner mitochondrial membrane, and into the matrix where they can either be [[Redox|oxidized]] and combined with [[coenzyme A]] to form CO{{sub|2}}, [[acetyl-CoA]], and [[NADH]],<ref name="Voet-2006" /> or they can be [[carboxylated]] (by [[pyruvate carboxylase]]) to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle and is therefore an [[anaplerotic reaction]], increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g., in [[striated muscle tissue|muscle]]) are suddenly increased by activity.<ref name="Stryer-1995">{{cite book | vauthors = Stryer L | title=In: Biochemistry. |chapter= Citric acid cycle. |edition= Fourth |location= New York |publisher= W.H. Freeman and Company|date= 1995 |pages= 509–527, 569–579, 614–616, 638–641, 732–735, 739–748, 770–773 |isbn= 0716720094 }}</ref>

In the citric acid cycle, all the intermediates (e.g. [[citrate]], [[Isocitric acid|iso-citrate]], [[Alpha-Ketoglutaric acid|alpha-ketoglutarate]], succinate, [[Fumaric acid|fumarate]], [[Malic acid|malate]] and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an [[Anaplerotic reactions|anaplerotic]] effect, and its removal has a cataplerotic effect. These anaplerotic and [[cataplerotic]] reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of [[Adenosine triphosphate|ATP]] production by the mitochondrion, and thus the availability of ATP to the cell.<ref name="Stryer-1995" />

Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the [[beta-oxidation]] of [[fatty acids]], is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO{{sub|2}} and water, with the energy thus released captured in the form of ATP.<ref name="Stryer-1995" />

In the liver, the [[carboxylation]] of [[cytosol]]ic pyruvate into intra-mitochondrial oxaloacetate is an early step in the [[gluconeogenesis|gluconeogenic]] pathway, which converts [[lactic acid|lactate]] and de-aminated [[alanine]] into glucose,<ref name="Voet-2006" /><ref name="Stryer-1995" /> under the influence of high levels of [[glucagon]] and/or [[epinephrine]] in the blood.<ref name="Stryer-1995" /> Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted to cytosolic oxaloacetate, and ultimately to glucose, in a process that is almost the reverse of [[glycolysis]].<ref name="Stryer-1995" />

The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of [[succinate dehydrogenase]], which is bound to the inner mitochondrial membrane as part of Complex II.<ref>{{cite journal | vauthors = King A, Selak MA, Gottlieb E | title = Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer | journal = Oncogene | volume = 25 | issue = 34 | pages = 4675–4682 | date = August 2006 | pmid = 16892081 | doi = 10.1038/sj.onc.1209594 | doi-access =  }}</ref> The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of [[NADH]] and one molecule of [[FADH2|FADH{{sub|2}}]]) that are a source of electrons for the [[electron transport chain]], and a molecule of [[Guanosine triphosphate|GTP]] (which is readily converted to an ATP).<ref name="Voet-2006"/>

==== O{{sub|2}} and NADH: energy-releasing reactions ====
{{Main|Oxidative phosphorylation|electron transport chain}}
[[File:Electron transport chain.svg|thumb|400px|Electron transport chain in the mitochondrial intermembrane space]]

The electrons from NADH and FADH{{sub|2}} are transferred to oxygen (O{{sub|2}}) and hydrogen (protons) in several steps via an electron transport chain. NADH and FADH{{sub|2}} molecules are produced within the matrix via the citric acid cycle and in the cytoplasm by [[glycolysis]]. [[Reducing equivalent]]s from the cytoplasm can be imported via the [[malate-aspartate shuttle]] system of [[antiporter]] proteins or fed into the electron transport chain using a [[glycerol phosphate shuttle]].<ref name="Voet-2006"/>

The major energy-releasing reactions<ref name="Voet-2004">{{cite book | vauthors = Voet D, Voet JG |title=Biochemistry |date=2004 |publisher=Wiley |location=New York, NY |isbn=978-0-471-19350-0 |edition=3rd | page = 804 }}</ref><ref name="Atkins-2006">{{cite book | vauthors = Atkins P, de Paula J | date = 2006 | chapter = Impact on biochemistry: Energy conversion in biological cells | title = Physical Chemistry | edition = 8th | pages = 225–229 | publisher = Freeman | location = New York | isbn = 978-0-7167-8759-4 }}</ref> that make the mitochondrion the "powerhouse of the cell" occur at [[Electron transport chain#Mitochondrial redox carriers|protein complexes I, III and IV]] in the inner mitochondrial membrane ([[NADH dehydrogenase (ubiquinone)]], [[Coenzyme Q - cytochrome c reductase|cytochrome c reductase]], and [[cytochrome c oxidase]]). At [[complex IV]], O<sub>2</sub> reacts with the reduced form of iron in [[cytochrome c]]:

:{{chem2 | O2 + 4 H+(aq) + 4 Fe(2+)(cyt c) -> 2 H2O + 4 Fe(3+)(cyt c) }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -218 kJ/mol

releasing a lot of [[Gibbs free energy|free energy]]<ref name="Atkins-2006"/><ref name="Voet-2004"/> from the reactants without breaking bonds of an organic fuel. The free energy put in to remove an electron from Fe<sup>2+</sup> is released at [[complex III]] when Fe<sup>3+</sup> of cytochrome c reacts to oxidize [[ubiquinol]] (QH<sub>2</sub>):

:{{chem2 | 2 Fe(3+)(cyt c) + QH2 -> 2 Fe(2+)(cyt c) + Q + 2 H+(aq) }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -30 kJ/mol

The [[ubiquinone]] (Q) generated reacts, in [[complex I]], with NADH:

:{{chem2 |Q + H+(aq) + NADH -> QH2 + NAD+ }}{{spaces|4}}Δ<sub>r</sub>G<sup>o'</sup> = -81 kJ/mol

While the reactions are controlled by an electron transport chain, free electrons are not amongst the reactants or products in the three reactions shown and therefore do not affect the free energy released, which is used to pump [[Hydrogen ion|protons]] (H{{sup|+}}) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming [[reactive oxygen species]] such as [[superoxide]].<ref name="Voet-2006" /> This can cause [[oxidative stress]] in the mitochondria and may contribute to the decline in mitochondrial function associated with aging.<ref name="Huang-2004">{{cite journal | vauthors = Huang H, Manton KG | title = The role of oxidative damage in mitochondria during aging: a review | journal = Frontiers in Bioscience | volume = 9 | issue = 1–3 | pages = 1100–1117 | date = May 2004 | pmid = 14977532 | doi = 10.2741/1298 }}</ref>

As the proton concentration increases in the intermembrane space, a strong [[electrochemical gradient]] is established across the inner membrane. The protons can return to the matrix through the [[ATP synthase]] complex, and their potential energy is used to synthesize [[Adenosine triphosphate|ATP]] from ADP and inorganic phosphate (P{{sub|i}}).<ref name="Voet-2006"/> This process is called [[chemiosmosis]], and was first described by [[Peter D. Mitchell|Peter Mitchell]],<ref name="Mitchell-1967a">{{cite journal | vauthors = Mitchell P, Moyle J | title = Chemiosmotic hypothesis of oxidative phosphorylation | journal = Nature | volume = 213 | issue = 5072 | pages = 137–139 | date = January 1967 | pmid = 4291593 | doi = 10.1038/213137a0 | bibcode = 1967Natur.213..137M }}</ref><ref name="Mitchell-1967b">{{cite journal | vauthors = Mitchell P | title = Proton current flow in mitochondrial systems | journal = Nature | volume = 214 | issue = 5095 | pages = 1327–1328 | date = June 1967 | pmid = 6056845 | doi = 10.1038/2141327a0 | bibcode = 1967Natur.214.1327M }}</ref> who was awarded the 1978 [[Nobel Prize in Chemistry]] for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to [[Paul D. Boyer]] and [[John E. Walker]] for their clarification of the working mechanism of ATP synthase.<ref>{{cite web |last =Nobel Foundation |title =Chemistry 1997 |url =http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |access-date =December 16, 2007 |archive-date =July 8, 2007 |archive-url =https://web.archive.org/web/20070708165350/http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |url-status =live }}</ref>

====Heat production====
Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as ''proton leak'' or [[mitochondrial uncoupling]] and is due to the [[facilitated diffusion]] of protons into the matrix. The process results in the unharnessed potential energy of the proton [[Electrochemistry|electrochemical]] gradient being released as heat.<ref name="Voet-2006"/> The process is mediated by a proton channel called [[thermogenin]], or [[UCP1]].<ref name="Mozo-2005">{{cite journal | vauthors = Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F | title = Thermoregulation: what role for UCPs in mammals and birds? | journal = Bioscience Reports | volume = 25 | issue = 3–4 | pages = 227–249 | date = November 2005 | pmid = 16283555 | doi = 10.1007/s10540-005-2887-4 }}</ref> Thermogenin is primarily found in [[brown adipose tissue]], or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.<ref name="Mozo-2005"/>