Does Anaerobic Respiration Continue to Citric Acid

I think both @David and @SatwikPasani have given nice answers, but none of them seems complete and involving all details. So I am posting another answer which involves much of the required details for benefit of readers as well as myself.

The simplest answer would be that cell switches from aerobic to anaerobic respiration via allosteric inhibition of enzymes from product build-up. The details, in a stepwise manner, go as follows:

• In the absence of oxygen, mitochondria activate a factor known as hypoxia-inducible factor-1 (HIF-1)¹. HIF-1 helps in slowly shutting down the electron transport chain. This happens as HIF-1 induces subunit switching from cytochrome-c oxidase subunit 4 isoform 1 (COX_4-1) to COX_4-2 ². Also, HIF-1 induces activation of micro-RNA 210 (mir-210)³, which blocks expression of iron-sulfur cluster assembly proteins ISCU1/2⁴, which are required for the function of complex I⁵, COX₁₀ ⁶, aconitase and subunit D of succinate dehydrogenase. Apart from this, in decreased levels of O₂, nitric oxide (NO) causes inhibition of respiration and even cell death⁷. Also, nitric oxide synthase is a target of HIF-1⁸. You can understand this by this diagram⁹:

  

• Now, shutting down electron transport chain causes accumulation of NADH (and FADH₂) in the mitochondrion. This build up, in turn, shuts another process known as malate-aspartate shuttle (MA shuttle), which is essentially a process to indirectly transfer NADH from cytosol to mitochondrion since mitochondrial membrane is impermeable to NADH¹⁰. Now, since malate-aspartate shuttle is not working anymore, thus NADH remains in the cytosol. See this through the diagram below:

  

• Another point is that accumulation of NADH in the mitochondrion shuts down krebs cycle. It is so because two of the main enzymes, isocitrate dehydrogenase and $\alpha$-ketoglutarate dehydrogenase, both of which require the presence of NAD⁺ to function, are inhibited by the presence of NADH¹¹. Also, aconitase and succinate dehydrogenase are inhibited by mir-210 as already discussed. Thus, inhibition of krebs cycle occurs, which leads to accumulation of acetyl-coA. See the diagram below:

  

• Now, accumulation of both NADH and acetyl-coA inhibit the activity of pyruvate dehydrogenase¹², which leads to accumulation of pyruvic acid in the mitochondrion. This is also clear from the above diagram.

• Now, since pyruvic acid is not being metabolized, it is hence no more transported from cytosol to mitochondrion. Transportation of pyruvic acid from cytosol (after glycolysis) to mitochondrion (for krebs cycle) requires mitochondrial pyruvate carrier (MPC). Now, presence of malate is shown to promote the activity of MPC¹³. But since krebs cycle has already stopped, so no more malate is being produced. Also, since malate is not metabolized through MA shuttle (see second point), so it travels back into the cytoplasm (or is not produced at all). Thus, activity of MPC is significantly reduced. Apart from this, $\alpha$-keto acids are known to inhibit the activity of MPC¹⁴. Thus, due to accumulation of $\alpha$-ketoglutarate (which is not metabolized by $\alpha$-ketoglutarate dehydrogenase, see third point), activity of MPC is further reduced. Because of these effects, pyruvate remains in the cytosol. See the following diagram for clarification¹⁵:

  

• In the last step, accumulation of pyruvic acid as well as of NADH in the cytosol together promote anaerobic respiration since in this process, NADH is converted to NAD⁺, which is possible due to the presence of NADH. This is also helpful since it not only helps in decreasing the accumulation of cytosolic NADH, but also in metabolizing the NADH generated from glycolysis. Finally, the complete process can be visualized by the following diagram:

  

P.S.: However, accumulation of lactate does not happen (i.e. a question like What if excess lactate inhibits anaerobic respiration? would not make sense) because lactate is readily removed from the cytosol to outside the cell so that it is transported to the liver, where it is converted back into glucose. This process is known as Cori Cycle¹⁶. See this diagram:

Bonus: A novel research has concluded that extracellular acidosis (induced by release of lactic acid), causes a dramatic increase in efficiency of ATP production by mitochondria during hypoxia(!). Under neutral hypoxia (without acidosis), mitochondria get fragmented and lead to impaired ATP production, causing cell death. But under acidosis-hypoxia, mitochondria become unusually elongated (by inhibiting DRP1-mediated mitochondrial fission¹⁷ and inducing mitochondrial fusion via Stress-Induced Mitochondrial Hyperfusion (SIMH) pathway¹⁸), cristae get remodelled through OPA1¹⁹ which protects and maintains ATP production in the cell in hypoxia. See this diagram:

Since the whole process is reversible (by bringing extracellular pH to neutral), thus a dynamic equilibrium can be attained in cells with high oxygen demand, like neurons, through which cell can maintain high ATP production even in hypoxia.

References:

_{1. Giancarlo Solaini, Alessandra Baracca, Giorgio Lenaz, Gianluca Sgarbi, Hypoxia and mitochondrial oxidative metabolism, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1797, Issues 6–7, June–July 2010, Pages 1171-1177, ISSN 0005-2728, http://doi.org/10.1016/j.bbabio.2010.02.011.}

_{2. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111–122, 2007}

_{3. Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT, Giaccia AJ. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 35: 856–867, 2009}

_{4. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10: 273–284, 2009}

_{5. Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, Fourre S, Magnone V, Ricci JE, Pouyssegur J, Gounon P, Hofman P, Barbry P, Mari B. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ. 2010. October 1}

_{6. Chen Z, Li Y, Zhang H, Huang P, Luthra R. Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29: 4362–4368}

_{7. Lee VY, McClintock DS, Santore MT, Budinger GR, Chandel NS. Hypoxia sensitizes cells to nitric oxide-induced apoptosis. J Biol Chem 277: 16067–16074, 2002}

_{8. Jung F, Palmer LA, Zhou N, Johns RA. Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circ Res 86: 319–325, 2000}

_{9. Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. American Journal of Physiology - Cell Physiology. 2011;300(3):C385-C393. doi:10.1152/ajpcell.00485.2010.}

_{10. Wikipedia contributors. "Malate-aspartate shuttle." Wikipedia, The Free Encyclopedia. Wikipedia, The Free Encyclopedia, 7 Mar. 2017. Web. 7 Apr. 2017.}

_{11. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 17.2, Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled.}

_{12. Budde RJA, Fang TK, Randall DD, Miernyk JA. Acetyl-Coenzyme A Can Regulate Activity of the Mitochondrial Pyruvate Dehydrogenase Complex in Situ. Plant Physiology. 1991;95(1):131-136.}

_{13. Mowbray A. Evidence for the role of a specific monocarboxylate transporter in the control of pyruvate oxidation by rat liver mitochondria. FEBS Lett. 1974;44:344–347. doi: 10.1016/0014-5793(74)81174-9}

_{14. Halestrap AP, Brand MD, Denton RM. Inhibition of mitochondrial pyruvate transport by phenylpyruvate and alpha-ketoisocaproate. Biochim Biophys Acta. 1974;367:102–108. doi: 10.1016/0005-2736(74)90140-0.}

_{15. Schell JC, Rutter J. The long and winding road to the mitochondrial pyruvate carrier. Cancer & Metabolism. 2013;1:6. doi:10.1186/2049-3002-1-6.}

_{16. Wikipedia contributors. "Cori cycle." Wikipedia, The Free Encyclopedia. Wikipedia, The Free Encyclopedia, 28 Feb. 2017. Web. 7 Apr. 2017.}

_{17. Smirnova, E., Griparic, L., Shurland, D. L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).}

_{18. Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589–1600 (2009).}

_{19. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).}

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Source: https://biology.stackexchange.com/questions/43701/how-does-the-body-switch-between-aerobic-and-anaerobic-respiration

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