Editing Oxidative phosphorylation (section)

=== Endotherms ===

==== Hypoxia/anoxia intolerance ====
Most mammals and birds are intolerant to low/no oxygen conditions. For the heart, in the absence of oxygen, the first four [[Electron transport chain|complexes]] of the electron transport chain decrease in activity.<ref name="Lesnefsky_2017" /> This will lead to protons leaking through the [[inner mitochondrial membrane]] without complexes [[Respiratory complex I|I]], [[Complex III|III]], and [[Complex IV|IV]] pushing protons back through to maintain the proton gradient. There is also electron leak (an event where electrons leak out of the electron transport chain), which happens because [[Nadh dehydrogenase|NADH dehydrogenase]] within Complex I becomes damaged, which allows for the production of ROS ([[reactive oxygen species]]) during ischemia.<ref name="Chen_2007">{{cite journal | vauthors = Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ | title = Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion | journal = American Journal of Physiology. Cell Physiology | volume = 292 | issue = 1 | pages = C137-C147 | date = January 2007 | pmid = 16971498 | doi = 10.1152/ajpcell.00270.2006 }}</ref> This will lead to the reversing of [[ATP synthase|Complex V]], which forces protons from the [[Mitochondrial matrix|matrix]] back into the [[Intermembrane space|inner membrane space]], against their [[Fick's laws of diffusion|concentration gradient]]. Forcing protons against their concentration gradient requires energy, so Complex V uses up ATP as an energy source.<ref name="St-Pierre_2000">{{cite journal | vauthors = St-Pierre J, Brand MD, Boutilier RG | title = Mitochondria as ATP consumers: cellular treason in anoxia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 15 | pages = 8670–8674 | date = July 2000 | pmid = 10890886 | pmc = 27006 | doi = 10.1073/pnas.140093597 | doi-access = free | bibcode = 2000PNAS...97.8670S }}</ref>

==== Reoxygenation of intolerant animals ====
When oxygen re-enters the system, animals are faced with a different set of problems. Since ATP was used up during the anoxic period, it leads to a lack of [[ADP-ribose diphosphatase|ADP]] within the system.<ref name="Bundgaard_2019">{{cite journal | vauthors = Bundgaard A, James AM, Gruszczyk AV, Martin J, Murphy MP, Fago A | title = Metabolic adaptations during extreme anoxia in the turtle heart and their implications for ischemia-reperfusion injury | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 2850 | date = February 2019 | pmid = 30808950 | pmc = 6391391 | doi = 10.1038/s41598-019-39836-5 | bibcode = 2019NatSR...9.2850B }}</ref> This is due to ADP's natural degradation into AMP, resulting in ADP being drained from the system. With no ADP in the system, Complex V is unable to start, meaning the protons will not flow through it to enter the matrix.<ref name="Bundgaard_2019" /> Due to Complex V's reversal during anoxia, the proton gradient has become hyperpolarized (where the proton gradient is highly positively charged). Another factor in this problem is that [[Succinic acid|succinate]] built up during anoxia, so when oxygen is reintroduced, succinate donates electrons to [[Succinate dehydrogenase|Complex II]].<ref name="Bundgaard_2024">{{cite journal | vauthors = Bundgaard A, Borowiec BG, Lau GY | title = Are reactive oxygen species always bad? Lessons from hypoxic ectotherms | journal = The Journal of Experimental Biology | volume = 227 | issue = 6 | pages = jeb246549 | date = March 2024 | pmid = 38533673 | doi = 10.1242/jeb.246549 | bibcode = 2024JExpB.227B6549B }}</ref><ref name="Chouchani_2014">{{cite journal | vauthors = Chouchani ET, Pell VR, Gaude E, Aksentijević D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP | title = Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS | journal = Nature | volume = 515 | issue = 7527 | pages = 431–435 | date = November 2014 | pmid = 25383517 | pmc = 4255242 | doi = 10.1038/nature13909 | bibcode = 2014Natur.515..431C }}</ref> The hyperpolarized gradient and succinate buildup leads to [[Reverse electron flow|reverse electron transport]], causing [[oxidative stress]],<ref name="Murphy_2009">{{cite journal | vauthors = Murphy MP | title = How mitochondria produce reactive oxygen species | journal = The Biochemical Journal | volume = 417 | issue = 1 | pages = 1–13 | date = January 2009 | pmid = 19061483 | pmc = 2605959 | doi = 10.1042/BJ20081386 }}</ref> which can lead to cellular damage and diseases.<ref name="Bolisetty_2013">{{cite journal | vauthors = Bolisetty S, Jaimes EA | title = Mitochondria and reactive oxygen species: physiology and pathophysiology | journal = International Journal of Molecular Sciences | volume = 14 | issue = 3 | pages = 6306–6344 | date = March 2013 | pmid = 23528859 | pmc = 3634422 | doi = 10.3390/ijms14036306 | doi-access = free }}</ref>

==== Hypoxia/anoxia tolerance ====
The naked mole rat ([[Naked mole-rat|''Heterocephalus glaber'']]) is a hypoxia-tolerant species that sleeps in deep burrows and in large colonies. The depth of these burrows reduces access to oxygen, and sleeping in large groups will deplete the area of oxygen quicker than usual, leading to hypoxia.<ref name="Pamenter_2018" /> The naked mole rat has the unique ability to survive low oxygen conditions for no less than several hours, and zero oxygen conditions for 18 minutes.<ref name="Eaton_2023">{{cite journal | vauthors = Eaton L, Wang T, Roy M, Pamenter ME | title = Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During ''In Vitro'' Hypoxia or Ischemia and Reperfusion | journal = Current Neuropharmacology | volume = 21 | issue = 6 | pages = 1450–1461 | date = 2023 | pmid = 35339183 | pmc = 10324332 | doi = 10.2174/1570159X20666220327220929 }}</ref> One of the ways of combatting hypoxia in the brain is decreasing the reliance on oxygen for ATP production, achieved by decreased respiration rates and proton leak.<ref name="Pamenter_2018" />

==== Reoxygenation of tolerant animals ====
Hypoxia/anoxia tolerant species handle ROS production during reoxygenation better than the intolerant. In the cortex of the naked mole rats, they show better homeostasis of ROS production than intolerant species and seem to lack the burst of ROS that typically comes with reoxygenation.<ref name="Eaton_2023" />