Editing Lactic acid (section)

==Biology==
===Molecular biology===
{{sc|L}}-Lactic acid is the primary [[endogenous]] [[agonist]] of [[hydroxycarboxylic acid receptor&nbsp;1]] (HCA<sub>1</sub>), a {{nowrap|[[Gi alpha subunit|G<sub>i/o</sub>-coupled]]}} [[G protein-coupled receptor]] (GPCR).<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" />

===Metabolism and exercise===
{{See also|N-Lactoylphenylalanine}}
During power exercises such as [[sprint (running)|sprinting]], when the rate of demand for energy is high, [[glucose]] is broken down and oxidized to [[pyruvate]], and lactate is then produced from the pyruvate faster than the body can process it, causing lactate concentrations to rise. The production of lactate is beneficial for [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] regeneration (pyruvate is reduced to lactate while NADH is oxidized to NAD<sup>+</sup>), which is used up in oxidation of [[glyceraldehyde 3-phosphate]] during production of pyruvate from glucose, and this ensures that energy production is maintained and exercise can continue. During intense exercise, the respiratory chain cannot keep up with the amount of hydrogen ions that join to form NADH, and cannot regenerate NAD<sup>+</sup> quickly enough, so pyruvate is converted to lactate to allow energy production by [[glycolysis]] to continue.<ref name="Ferguson 2018">{{cite journal | last1=Ferguson | first1=Brian S. | last2=Rogatzki | first2=Matthew J. | last3=Goodwin | first3=Matthew L. | last4=Kane | first4=Daniel A. | last5=Rightmire | first5=Zachary | last6=Gladden | first6=L. Bruce | title=Lactate metabolism: historical context, prior misinterpretations, and current understanding | journal=European Journal of Applied Physiology | volume=118 | date=2018 | issue=4 | issn=1439-6319 | doi=10.1007/s00421-017-3795-6 | pages=691–728| pmid=29322250 }}</ref>

The resulting lactate can be used in two ways:
* [[Oxidation]] back to [[pyruvate]] by well-oxygenated [[muscle]] cells, heart cells, and brain cells
** Pyruvate is then directly used to fuel the [[Krebs cycle]]
* Conversion to [[glucose]] via [[gluconeogenesis]] in the liver and release back into circulation by means of the [[Cori cycle]]<ref name=mcardlekatch>{{Cite book|vauthors=McArdle WD, Katch FI, Katch VL|title=Exercise Physiology: Energy, Nutrition, and Human Performance|year=2010|publisher=Wolters Kluwer/Lippincott Williams & Wilkins Health|isbn=978-0-683-05731-7|url-access=registration|url=https://archive.org/details/exercisephysiolo00mcar_0}}</ref>
** If blood glucose concentrations are high, the glucose can be used to build up the liver's [[glycogen]] stores.

Lactate is continually formed at rest and during all exercise intensities. Lactate serves as a metabolic fuel being produced and oxidatively disposed in resting and exercising muscle and other tissues.<ref name="Ferguson 2018" /> Some sources of excess lactate production are metabolism in [[red blood cell]]s, which lack [[mitochondria]] that perform aerobic respiration, and limitations in the rates of enzyme activity in muscle fibers during intense exertion.<ref name=mcardlekatch/> [[Lactic acidosis]] is a [[physiology|physiological condition]] characterized by accumulation of lactate (especially {{sc|L}}-lactate), with formation of an excessively high proton concentration [H<sup>+</sup>] and correspondingly low [[pH]] in the tissues, a form of [[metabolic acidosis]].<ref name="Ferguson 2018" />

The first stage in metabolizing glucose is [[glycolysis]], the conversion of glucose to pyruvate<sup>−</sup> and H<sup>+</sup>:

:{{chem2|C6H12O6 + 2 NAD+ + 2 ADP(3-) + 2 HPO4(2-) -> 2 CH3COCO2- + 2 H+ + 2 NADH + 2 ATP(4-) + 2 H2O}}

When sufficient oxygen is present for aerobic respiration, the pyruvate is oxidized to {{chem2|CO2}} and water by the Krebs cycle, in which [[oxidative phosphorylation]] generates ATP for use in powering the cell.
When insufficient oxygen is present, or when there is insufficient capacity for pyruvate oxidation to keep up with rapid pyruvate production during intense exertion, the pyruvate is converted to lactate<sup>−</sup> by [[lactate dehydrogenase]]), a process that absorbs these protons:<ref name=Robergs>{{cite journal | vauthors = Robergs RA, Ghiasvand F, Parker D | title = Biochemistry of exercise-induced metabolic acidosis | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 287 | issue = 3 | pages = R502–R516 | date = September 2004 | pmid = 15308499 | doi = 10.1152/ajpregu.00114.2004 | s2cid = 2745168 }}</ref>

:{{chem2|2 CH3COCO2- + 2 H+ + 2 NADH -> 2 CH3CH(OH)CO2- + 2 NAD+}}

The combined effect is:

:{{chem2|C6H12O6 + 2 ADP(3-) + 2HPO4(2-) -> 2 CH3CH(OH)CO2- + 2 ATP(4-) + 2 H2O}}

The production of lactate from glucose ({{chem2|glucose → 2 lactate- + 2 H+}}), when viewed in isolation, releases two H<sup>+</sup>. The H<sup>+</sup> are absorbed in the production of ATP, but H<sup>+</sup> is subsequently released during hydrolysis of ATP:

:{{chem2|ATP(4−) + H2O → ADP(3-) + HPO4(2-) + H+}}

Once the production and use of ATP is included, the overall reaction is

:{{chem2|C6H12O6 -> 2 CH3CH(OH)CO2- + 2 H+}}

The resulting increase in acidity persists until the excess lactate and protons are converted back to pyruvate, and then to glucose for later use, or to {{chem2|CO2}} and water for the production of ATP.<ref name="Ferguson 2018" />

=== Neural tissue energy source ===
Although [[glucose]] is usually assumed to be the main energy source for living tissues, there is evidence that lactate, in preference to  glucose, is preferentially metabolized by [[neuron]]s in the [[brain]]s of several [[mammalian]] species that include [[mouse|mice]], [[rat]]s, and [[human]]s.<ref name=zilberter2010/><ref>{{cite journal | vauthors = Wyss MT, Jolivet R, Buck A, Magistretti PJ, Weber B | title = In vivo evidence for lactate as a neuronal energy source | journal = The Journal of Neuroscience | volume = 31 | issue = 20 | pages = 7477–85 | date = May 2011 | pmid = 21593331 | pmc = 6622597 | doi = 10.1523/JNEUROSCI.0415-11.2011 | url = http://www.zora.uzh.ch/55080/1/Wyss_Weber_J_Neuroscience%282011%29.pdf }}</ref><ref name="Ferguson 2018" />  According to the [[lactate shuttle|lactate-shuttle hypothesis]], [[glia]]l cells are responsible for transforming glucose into lactate, and for providing lactate to the neurons.<ref>{{cite journal | vauthors = Gladden LB | title = Lactate metabolism: a new paradigm for the third millennium | journal = The Journal of Physiology | volume = 558 | issue = Pt 1 | pages = 5–30 | date = July 2004 | pmid = 15131240 | pmc = 1664920 | doi = 10.1113/jphysiol.2003.058701 }}</ref><ref>{{cite journal | vauthors = Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, Magistretti PJ | title = Activity-dependent regulation of energy metabolism by astrocytes: an update | journal = Glia | volume = 55 | issue = 12 | pages = 1251–62 | date = September 2007 | pmid = 17659524 | doi = 10.1002/glia.20528 | s2cid = 18780083 }}</ref> Because of this local metabolic activity of glial cells, the [[extracellular fluid]] immediately surrounding neurons strongly differs in composition from the [[blood]] or [[cerebrospinal fluid]], being much richer with lactate, as was found in [[microdialysis]] studies.<ref name=zilberter2010>{{cite journal | vauthors = Zilberter Y, Zilberter T, Bregestovski P | title = Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis | journal = Trends in Pharmacological Sciences | volume = 31 | issue = 9 | pages = 394–401 | date = September 2010 | pmid = 20633934 | doi = 10.1016/j.tips.2010.06.005 }}</ref>

=== Brain development metabolism ===
Some evidence suggests that lactate is important at early stages of development for brain metabolism in [[prenatal]] and early [[postnatal]] subjects, with lactate at these stages having higher concentrations in body liquids, and being utilized by the brain preferentially over glucose.<ref name=zilberter2010/> It was also hypothesized that lactate may exert a strong action over [[GABA]]ergic networks in the [[brain development|developing brain]], making them more [[inhibitory]] than it was previously assumed,<ref>{{cite journal | vauthors = Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y | title = Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro | journal = Journal of Neurochemistry | volume = 112 | issue = 4 | pages = 900–12 | date = February 2010 | pmid = 19943846 | doi = 10.1111/j.1471-4159.2009.06506.x | s2cid = 205621542 | doi-access = free }}</ref> acting either through better support of metabolites,<ref name=zilberter2010/> or alterations in base intracellular [[pH]] levels,<ref>{{cite journal | vauthors = Tyzio R, Allene C, Nardou R, Picardo MA, Yamamoto S, Sivakumaran S, Caiati MD, Rheims S, Minlebaev M, Milh M, Ferré P, Khazipov R, Romette JL, Lorquin J, Cossart R, Khalilov I, Nehlig A, Cherubini E, Ben-Ari Y | title = Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate | journal = The Journal of Neuroscience | volume = 31 | issue = 1 | pages = 34–45 | date = January 2011 | pmid = 21209187 | pmc = 6622726 | doi = 10.1523/JNEUROSCI.3314-10.2011 }}</ref><ref>{{cite journal | vauthors = Ruusuvuori E, Kirilkin I, Pandya N, Kaila K | title = Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism | journal = The Journal of Neuroscience | volume = 30 | issue = 46 | pages = 15638–42 | date = November 2010 | pmid = 21084619 | pmc = 6633692 | doi = 10.1523/JNEUROSCI.3355-10.2010 }}</ref> or both.<ref>{{cite journal | vauthors = Khakhalin AS | title = Questioning the depolarizing effects of GABA during early brain development | journal = Journal of Neurophysiology | volume = 106 | issue = 3 | pages = 1065–7 | date = September 2011 | pmid = 21593390 | doi = 10.1152/jn.00293.2011 | s2cid = 13966338 }}</ref>

Studies of brain slices of mice show that [[beta-hydroxybutyrate|β-hydroxybutyrate]], lactate, and pyruvate act as oxidative energy substrates, causing an increase in the NAD(P)H oxidation phase, that glucose was insufficient as an energy carrier during intense synaptic activity and, finally, that lactate can be an efficient energy substrate capable of sustaining and enhancing brain aerobic energy metabolism ''in vitro''.<ref>{{cite journal | vauthors = Ivanov A, Mukhtarov M, Bregestovski P, Zilberter Y | title = Lactate Effectively Covers Energy Demands during Neuronal Network Activity in Neonatal Hippocampal Slices | journal = Frontiers in Neuroenergetics | volume = 3 | pages = 2 | year = 2011 | pmid = 21602909 | pmc = 3092068 | doi = 10.3389/fnene.2011.00002 | doi-access = free }}</ref> The study "provides novel data on biphasic NAD(P)H fluorescence transients, an important physiological response to neural activation that has been reproduced in many studies and that is believed to originate predominantly from activity-induced concentration changes to the cellular NADH pools."<ref>{{cite journal | vauthors = Kasischke K | title = Lactate fuels the neonatal brain | journal = Frontiers in Neuroenergetics | volume = 3 | pages = 4 | year = 2011 | pmid = 21687795 | pmc = 3108381 | doi = 10.3389/fnene.2011.00004 | doi-access = free }}</ref>

Lactate can also serve as an important source of energy for other organs, including the heart and liver. During physical activity, up to 60% of the heart muscle's energy turnover rate derives from lactate oxidation.<ref name="Parks"/>