Editing Oxidative phosphorylation (section)

== In hypoxic/anoxic conditions ==
As [[oxygen]] is fundamental for oxidative phosphorylation, a shortage in O<sub>2</sub> level can alter ATP production rates. The proton motive force and ATP production can be maintained by intracellular acidosis.<ref>{{cite journal | vauthors = Devaux JB, Hedges CP, Birch N, Herbert N, Renshaw GM, Hickey AJ | title = Acidosis Maintains the Function of Brain Mitochondria in Hypoxia-Tolerant Triplefin Fish: A Strategy to Survive Acute Hypoxic Exposure? | journal = Frontiers in Physiology | volume = 9 | pages = 1941 | date = January 2019 | pmid = 30713504 | pmc = 6346031 | doi = 10.3389/fphys.2018.01941 | doi-access = free }}</ref> Cytosolic protons that have accumulated with ATP hydrolysis and [[lactic acidosis]] can freely diffuse across the mitochondrial outer-membrane and acidify the inter-membrane space, hence directly contributing to the proton motive force and ATP production.

When exposed to [[Hypoxia (medicine)|hypoxia]]/anoxia (no oxygen), most animals will see damage done to their mitochondria.<ref name="Lesnefsky_2017">{{cite journal | vauthors = Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL | title = Mitochondrial Dysfunction and Myocardial Ischemia-Reperfusion: Implications for Novel Therapies | journal = Annual Review of Pharmacology and Toxicology | volume = 57 | pages = 535–565 | date = January 2017 | pmid = 27860548 | pmc = 11060135 | doi = 10.1146/annurev-pharmtox-010715-103335 }}</ref> From some species, these conditions can happen due to environmental variables, such as low tides,<ref name="Hickey_2012">{{cite journal | vauthors = Hickey AJ, Renshaw GM, Speers-Roesch B, Richards JG, Wang Y, Farrell AP, Brauner CJ | title = A radical approach to beating hypoxia: depressed free radical release from heart fibres of the hypoxia-tolerant epaulette shark (Hemiscyllum ocellatum) | journal = Journal of Comparative Physiology B | volume = 182 | issue = 1 | pages = 91–100 | date = January 2012 | pmid = 21748398 | doi = 10.1007/s00360-011-0599-6 }}</ref> low temperatures,<ref name="Hawrysh_2022">{{cite journal | vauthors = Hawrysh PJ, Myrka AM, Buck LT | title = Review: A history and perspective of mitochondria in the context of anoxia tolerance | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 260 | pages = 110733 | date = 2022 | pmid = 35288242 | doi = 10.1016/j.cbpb.2022.110733 }}</ref> or general living conditions, like living in a hypoxic underground burrow.<ref name="Pamenter_2018">{{cite journal | vauthors = Pamenter ME, Lau GY, Richards JG, Milsom WK | title = Naked mole rat brain mitochondria electron transport system flux and H<sup>+</sup> leak are reduced during acute hypoxia | journal = The Journal of Experimental Biology | volume = 221 | issue = Pt 4 | pages = jeb171397 | date = February 2018 | pmid = 29361591 | doi = 10.1242/jeb.171397 }}</ref> In humans, these conditions are commonly met in medical emergencies such as [[stroke]]s, [[ischemia]], and [[asphyxia]].

Despite this, or perhaps due to it, some species have developed their own defense mechanisms against anoxia/hypoxia, as well as during [[Reperfusion therapy|reperfusion]]/reoxygenation. These mechanisms are diverse and differ between [[endotherm]]s and [[ectotherm]]s and can differ even at the species level.

=== 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" />

=== Ectotherms ===

==== Hypoxia/anoxia intolerance ====
Research on intolerant ectotherms is more limited than on tolerant ectotherms and intolerant endotherms, but it is shown that anoxia/hypoxia intolerance is different in terms for how long the intolerant survive as opposed to the tolerant between endotherms and ectotherms. While intolerant endotherms only last minutes, intolerant ectotherms can last hours, such as subtidal scallops (''[[Argopecten irradians]]'').<ref name="Ivanina_2016">{{cite journal | vauthors = Ivanina AV, Nesmelova I, Leamy L, Sokolov EP, Sokolova IM | title = Intermittent hypoxia leads to functional reorganization of mitochondria and affects cellular bioenergetics in marine molluscs | journal = The Journal of Experimental Biology | volume = 219 | issue = Pt 11 | pages = 1659–1674 | date = June 2016 | pmid = 27252455 | doi = 10.1242/jeb.134700 | bibcode = 2016JExpB.219.1659I }}</ref> This difference in intolerance could be due to a couple of different factors. One advantage is that the ectothermic inner mitochondrial membrane is less leaky, so less protons will leak through the inner membrane due to differences in the [[Lipid bilayer|phospholipid bilayer]] composition.<ref name="St-Pierre_2000" /> Another advantage ectotherms tend to have in this category is an ability for their mitochondria to properly function in a wide range of temperatures, such as the western fence lizard (''[[Western fence lizard|Sceloporus occidentalis]]).'' While western fence lizards are not considered a hypoxia-tolerant animal, they still showed less temperature sensitivity in their mitochondria than mice mitochondria.<ref name="Berner_1999">{{cite journal | vauthors = Berner NJ | title = Oxygen consumption by mitochondria from an endotherm and an ectotherm | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 124 | issue = 1 | pages = 25–31 | date = September 1999 | pmid = 10582317 | doi = 10.1016/S0305-0491(99)00093-0 }}</ref>

==== Reoxygenation of intolerant animals ====
While it is unclear how reoxygenation affects intolerant ectotherms at the mitochondrial level, there is some research showing how some of them respond. In the hypoxia-sensitive shovelnose ray (''[[Eastern shovelnose ray|Aptychotrema rostrata]]),'' it is shown that ROS production is lower upon reoxygenation compared to rays only exposed to normoxia (normal oxygen levels).<ref name="Hickey_2012" /> This differs from the hypoxia-sensitive endotherm, which would see an increase in ROS production. However, the ray's levels were still higher than the more hypoxia-tolerant Epaulette shark (''[[Epaulette shark|Hemiscyllum ocellatum]]''), which potentially sees hypoxia due to the bouts of low tides that can be seen in reef platforms.<ref name="Hickey_2012" />  Subtidal scallops will see both a decrease in maximal respiration and a depolarization of the membrane during reoxygenation.<ref name="Ivanina_2016" />

==== Hypoxia/anoxia tolerance ====
Hypoxia/Anoxia tolerant ectotherms have shown unique strategies for surviving anoxia. Pond turtles, such as the painted turtle (''[[Painted turtle|Chrysemys picta bellii]]''), will experience anoxia during winter while they overwinter at the bottom of frozen ponds.<ref name="Hawrysh_2022" /> In their cardiac mitochondria, the reversing of Complex V,<ref name="Galli_2013">{{cite journal | vauthors = Galli GL, Lau GY, Richards JG | title = Beating oxygen: chronic anoxia exposure reduces mitochondrial F1FO-ATPase activity in turtle (Trachemys scripta) heart | journal = The Journal of Experimental Biology | volume = 216 | issue = Pt 17 | pages = 3283–3293 | date = September 2013 | pmid = 23926310 | pmc = 4074260 | doi = 10.1242/jeb.087155 | bibcode = 2013JExpB.216.3283G }}</ref>  the usage of ATP, and the build-up of succinate are all prevented during anoxia.<ref name="Bundgaard_2019" /> Crucian carps (''[[Crucian carp|Carassius carassius]]'') also overwinter in frozen ponds and show no loss membrane potential in their cardiac mitochondria during anoxia, but this relies on complexes I and III to be active.<ref name="Scott_2024">{{cite journal | vauthors = Scott MA, Fagernes CE, Nilsson GE, Stensløkken KO | title = Maintained mitochondrial integrity without oxygen in the anoxia-tolerant crucian carp | journal = The Journal of Experimental Biology | volume = 227 | issue = 20 | pages = jeb247409 | date = October 2024 | pmid = 38779846 | pmc = 11418198 | doi = 10.1242/jeb.247409 | bibcode = 2024JExpB.227B7409S }}</ref>

==== Reoxygenation of tolerant animals ====
Pond turtles are able to completely avoid ROS production upon reoxygenation.<ref name="Bundgaard_2023">{{cite journal | vauthors = Bundgaard A, Gruszczyk AV, Prag HA, Williams C, McIntyre A, Ruhr IM, James AM, Galli GL, Murphy MP, Fago A | title = Low production of mitochondrial reactive oxygen species after anoxia and reoxygenation in turtle hearts | journal = The Journal of Experimental Biology | volume = 226 | issue = 9 | pages = jeb245516 | date = May 2023 | pmid = 37066839 | pmc = 10184768 | doi = 10.1242/jeb.245516 | bibcode = 2023JExpB.226B5516B }}</ref> However, crucian carp cannot and are unable to prevent the death of brain cells upon reoxygenation.<ref name="Bundgaard_2020">{{Cite journal | vauthors = Bundgaard A, Ruhr IM, Fago A, Galli GL |date=April 2020 |title=Metabolic adaptations to anoxia and reoxygenation: New lessons from freshwater turtles and crucian carp |url=https://linkinghub.elsevier.com/retrieve/pii/S2451965020300028 |journal=Current Opinion in Endocrine and Metabolic Research |language=en |volume=11 |pages=55–64 |doi=10.1016/j.coemr.2020.01.002}}</ref>