Distribution and activity of mitochondria are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5'- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5'-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by "second control mechanisms," such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, allosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5'-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria, similarly, decline of antioxidative enzyme activities (e.g. in the elderly) enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.

Department of Psychiatry 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

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Mattson MP, Partin J. Evidence for mitochondrial control of neuronal polarity. J Neurosci Res. 1999;56(1):8–20. PubMed

Erecinska M, Cherian S, Silver IA. Energy metabolism in mammalian brain during development. Prog Neurobiol. 2004;73(6):397–445. PubMed

Hroudová J, Fišar Z. Connectivity between mitochondrial functions and psychiatric disorders. Psychiatry Clin Neurosci. 2011;65(2):130–141. PubMed

Chada SR, Hollenberck PJ. Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr Biol. 2004;14(14):1272–1276. PubMed

Chang DT, Reynolds IJ. Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience. 2006;141(2):727–736. PubMed

Cai Q, Sheng ZH. Mitochondrial transport and docking in axons. Exp Neurol. 2009;218(2):257–267. PubMed PMC

Overly CC, Rieff HI, Hollenberck PJ. Organelle motility and metabolism in axons vs dendrites of cultured hippocampal neurons. J Cell Sci. 1996;109(Pt 5):971–980. PubMed

Cocco T, Pacelli C, Sgobbo P, et al. Control of oxidative phosphorylation efficiency by complex I in brain mitochondria. Neurobiol Aging. 2009;30(4):622–629. PubMed

Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60(5):748–766. PubMed PMC

Kadenbach B, Ramzan R, Wen L, et al. New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms. Biochim Biophys Acta. 2010;1800(3):205–212. PubMed

Hirst J. Towards the molecular mechanism of respiratory complex I. Biochem J. 2009;425(2):327–339. PubMed

Tomitsuka E, Kita K, Esumi H. Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(7):258–265. PubMed PMC

Solmaz SR, Hunte C. Structure of complex III with bound cytochrome c in reduced state and definition of a minimal core interface for electron transfer. J Biol Chem. 2008;283(25):17542–17549. PubMed

Rodríguez-Hernández A, Cordero MD, Salviati L, et al. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy. 2009;5(1):19–32. PubMed

Chen Q, Vazquez EJ, Moghaddas S, et al. Production of reactive oxygen species by mitochondria. Central role of complex III. J Biol Chem. 2003;278(38):36027–36031. PubMed

Trumpower BL. The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex. J Biol Chem. 1990;265(20):11409–11412. PubMed

Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(Pt 2):335–344. PubMed PMC

Noji H, Yoshida M. The rotary machine in the cell, adenosine-5’-triphosphate synthase. J Biol Chem. 2001;276(3):1665–1668. PubMed

Zanotti F, Gnoni A, Mangiullo R, et al. Effect of the ATPase inhibitor protein IF1 on H+ translocation in the mitochondrial adenosine-5’-triphosphate synthase complex. Biochem Biophys Res Commun. 2009;384(1):43–48. PubMed

Kadenbach B. Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta. 2003;1604(2):77–94. PubMed

Papa S, Scacco S, Sardanelli AM, et al. Complex I and the cAMP cascade in human physiopathology. Biosci Rep. 2002;22(1):3–16. PubMed

Benard G, Bellance N, Jose C, et al. Multi-site control and regulation of mitochondrial energy production. Biochim Biophys Acta. 2010;1797(6-7):698–709. PubMed

Cairns CB, Walther J, Harken AH, et al. Mitochondrial oxidative phosphorylation thermodynamic efficiencies reflect physiological organ roles. Am J Physiol. 1998;274(5 Pt 2):R1376–1383. PubMed

Gnaiger E. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol. 2009;41(10):1837–1845. PubMed

Ramzan R, Staniek K, Kadenbach B, et al. Mitochondrial respiration and membrane potential are regulated by the allosteric adenosine-5’-triphosphate-inhibition of cytochrome c oxidase. Biochim Biophys Acta. 2010;1797(9):1672–1680. PubMed

Telford JE, Kilbride SM, Davey GP. Complex I is rate-limiting for oxygen consumption in the nerve terminal. J Biol Chem. 2009;284(14):9109–9114. PubMed PMC

Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144–148. PubMed

Mitchell P. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biol Rev. 1966;41:445–502. PubMed

Nicholls DG, Vesce S, Kirk L, et al. Interactions between mitochondrial bioenergetics and cytoplasmic calcium in cultured cerebellar granule cells. Cell Calcium. 2003;34(4-5):407–424. PubMed

Chance B, Williams GR. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem. 1955;217(1):409–427. PubMed

Mourier A, Devin A, Rigoulet M. Active proton leak in mitochondria: a new way to regulate substrate oxidation. Biochim Biophys Acta. 2010;1797(2):255–261. PubMed

Walsh C, Barrow S, Voronina S, et al. Modulation of calcium signalling by mitochondria. Biochim Biophys Acta. 2009;1787(11):1374–1382. PubMed

Kadenbach B, Hüttemann M, Arnold S, et al. Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase. Free Radic Biol Med. 2000;29(3-4):211–221. PubMed

McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev. 1990;70(2):391–425. PubMed

Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J Physiol. 2000;529(Pt 1):37–47. PubMed PMC

Lee I, Bender E, Arnold S, et al. New control of mitochondrial membrane potential and reactive oxygen species formation--a hypothesis. Biol Chem. 2001;382(12):1629–1636. PubMed

Viola HM, Hool LC. Qo site of mitochondrial complex III is the source of increased superoxide after transient exposure to hydrogen peroxide. J Mol Cell Cardiol. 2010;49(5):875–885. PubMed

Papa S, Scacco S, Sardanelli AM, et al. Complex I and the cAMP cascade in human physiopathology. Biosci Rep. 2002;22(1):3–16. PubMed

Napiwotzki J, Kadenbach B. Extramitochondrial adenosine- 5’-triphosphate/adenosine diphosphate-ratios regulate cytochrome c oxidase activity via binding to the cytosolic domain of subunit IV. Biol Chem. 1998;379(3):335–339. PubMed

Lee I, Bender E, Kadenbach B. Control of mitochondrial membrane potential and reactive oxygen species formation by reversible phosphorylation of cytochrome c oxidase. Mol Cell Biochem. 2002;234-235(1-2):63–70. PubMed

Bender E, Kadenbach B. The allosteric adenosine-5’- triphosphate-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett. 2000;466(1):130–134. PubMed

Arnold S, Kadenbach B. Cell respiration is controlled by adenosine-5’-triphosphate, an allosteric inhibitor of cytochrome-c oxidase. Eur J Biochem. 1997;249(1):350–354. PubMed

Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31(2):139–170. PubMed PMC

Goglia F, Moreno M, Lanni A. Action of thyroid hormones at the cellular level: the mitochondrial target. FEBS Lett. 1999;452(3):115–120. PubMed

Arnold S, Goglia F, Kadenbach B. 3,5-Diiodothyronine binds to subunit Va of cytochrome-c oxidase and abolishes the allosteric inhibition of respiration by adenosine-5’- triphosphate. Eur J Biochem. 1998;252(2):325–330. PubMed

Starkov AA. “Mild” uncoupling of mitochondria. Biosci Rep. 1997;17(3):273–279. PubMed

Harper ME, Brand MD. Hyperthyroidism stimulates mitochondrial proton leak and adenosine-5’-triphosphate turnover in rat hepatocytes but does not change the overall kinetics of substrate oxidation reactions. Can J Physiol Pharmacol. 1994;72(8):899–908. PubMed

Harper ME, Brand MD. The quantitative contributions of mitochondrial proton leak and adenosine-5’-triphosphate turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status. J Biol Chem. 1993;268(20):14850–14860. PubMed

Starkov AA, Simonyan RA, Dedukhova VI, et al. Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones. Biochim Biophys Acta. 1997;1318(1-2):173–183. PubMed

Brand MD, Turner N, Ocloo A, et al. Proton conductance and fatty acyl composition of liver mitochondria correlates with body mass in birds. Biochem J. 2003;376(Pt 3):741–748. PubMed PMC

Azzu V, Jastroch M, Divakaruni AS, et al. The regulation and turnover of mitochondrial uncoupling proteins. Biochim Biophys Acta. 2010;1797(6-7):785–791. PubMed PMC

Brand MD, Pakay JL, Ocloo A, et al. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J. 2005;392(Pt 2):353–362. PubMed PMC

Rial E, Rodríguez-Sánchez L, Gallardo-Vara E, et al. Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochim Biophys Acta. 2010;1797(6-7):800–806. PubMed

Wojtczak L, Schönfeld P. Effect of fatty acids on energy coupling processes in mitochondria. Biochim Biophys Acta. 1993;1183(1):41–57. PubMed

Samartsev VN, Marchik EI, Shamagulova LV. Free fatty acids as inducers and regulators of uncoupling of oxidative phosphorylation in liver mitochondria with participation of adenosine diphosphate/adenosine- 5’-triphosphate- and aspartate/glutamate- antiporter. Biochemistry (Mosc) 2011;76(2):217–224. PubMed

Kleinfeld AM, Chu P, Romero C. Transport of long-chain native fatty acids across lipid bilayer membranes indicates that transbilayer flip-flop is rate limiting. Biochemistry. 1997;36(46):14146–14158. PubMed

Kamp F, Hamilton JA. pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids. Proc Natl Acad Sci. 1992;89(23):11367–11370. PubMed PMC

Köhnke D, Ludwig B, Kadenbach B. A threshold membrane potential accounts for controversial effects of fatty acids on mitochondrial oxidative phosphorylation. FEBS Lett. 1993;336(1):90–94. PubMed

Di Paola M, Lorusso M. Interaction of free fatty acids with mitochondria: coupling, uncoupling and permeability transition. Biochim Biophys Acta. 2006;1757(9-10):1330–1337. PubMed

Ježek P, Modrianský M, Garlid KD. Inactive fatty acids are unable to flip-flop across the lipid bilayer. FEBS Lett. 1997;408(2):161–165. PubMed

Hagen T, Vidal-Puig A. Mitochondrial uncoupling proteins in human physiology and disease. Minerva Med. 2002;93(1):41–57. PubMed

Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature. 2002;415(6867):96–99. PubMed

Brand MD, Affourtit C, Esteves TC, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37(6):755–767. PubMed

Zaninovich AA. Role of uncoupling proteins uncoupling protein1, uncoupling protein2 and uncoupling protein3 in energy balance, type 2 diabetes and obesity. Synergism with the thyroid. Medicina (B Aires) 2005;65(2):163–169. PubMed

Wolkow CA, Iser WB. Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan. Ageing Res Rev. 2006;5(2):196–208. PubMed PMC

Pecqueur C, Couplan E, Bouillaud F, et al. Genetic and physiological analysis of the role of uncoupling proteins in human energy homeostasis. J Mol Med. 2001;79(1):48–56. PubMed

Douette P, Sluse FE. Mitochondrial uncoupling proteins: new insights from functional and proteomic studies. Free Radic Biol Med. 2006;40(7):1097–1107. PubMed

Boss O, Hagen T, Lowell BB. Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes. 2000;49(2):143–156. PubMed

Trenker M, Malli R, Fertschai I, et al. Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol. 2007;9(4):445–452. PubMed PMC

De Marchi U, Castelbou C, Demaurex N. Uncoupling protein 3 modulates the activity of Sarco/ endoplasmic reticulum Ca2+-adenosine-5’-triphosphatease (SERCA) by decreasing mitochondrial adenosine-5’-triphosphate production. J Biol Chem. 2011;286(37):32533–32541. PubMed PMC

Liu D, Chan SL, de Souza-Pinto NC, et al. Mitochondrial uncoupling protein4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Med. 2006;8(3):389–414. PubMed

Kwok KH, Ho PW, Chu AC, et al. Mitochondrial uncoupling protein5 is neuroprotective by preserving mitochondrial membrane potential, adenosine-5’-triphosphate levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med. 2010;49(6):1023–1035. PubMed

Beck V, Jabůrek M, Demina T, et al. Polyunsaturated fatty acids activate human uncoupling proteins 1 and 2 in planar lipid bilayers. FASEB J. 2007;21(4):1137–1144. PubMed

Chan SL, Liu D, Kyriazis GA, et al. Mitochondrial uncoupling protein-4 regulates calcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem. 2006;281(49):37391–37403. PubMed

Chu AC, Ho PW, Kwok KH, et al. Mitochondrial uncoupling protein4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and adenosine-5’-triphosphate deficiency in neurons and is interlinked with uncoupling protein2 expression. Free Radic Biol Med. 2009;46(6):810–820. PubMed

Rupprecht A, Sokolenko EA, Beck V, et al. Role of the transmembrane potential in the membrane proton leak. Biophys J. 2010;98(8):1503–1511. PubMed PMC

Klingenberg M, Echtay KS. Uncoupling proteins: the issues from a biochemist point of view. Biochim Biophys Acta. 2001;1504(1):128–143. PubMed

Ježek P, Jabùrek M, Garlid KD. Channel character of uncoupling protein-mediated transport. FEBS Lett. 2010;584(10):2135–2141. PubMed PMC

Woyda-Ploszczyca A, Jarmuszkiewicz W. Ubiquinol (QH2) functions as a negative regulator of purine nucleotide inhibition of Acanthamoeba castellanii mitochondrial uncoupling protein. Biochim Biophys Acta. 2011;1807(1):42–52. PubMed

Swida A, Woyda-Ploszczyca A, Jarmuszkiewicz W. Redox state of quinone affects sensitivity of Acanthamoeba castellanii mitochondrial uncoupling protein to purine nucleotides. Biochem J. 2008;413(2):359–367. PubMed

Echtay KS, Brand MD. Coenzyme Q induces GDP-sensitive proton conductance in kidney mitochondria. Biochem Soc Trans. 2001;29(Pt 6):763–768. PubMed

Ježek P, Hlavatá L. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol. 2005;37(12):2478–2503. PubMed

Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004;279(47):49064–49073. PubMed

Tretter L, Adam-Vizi V. Generation of reactive oxygen species in the reaction catalyzed by á-ketoglutarate dehydrogenase. J Neurosci. 2004;24(36):7771–7778. PubMed PMC

Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13. PubMed PMC

Brand MD, Affourtit C, Esteves TC, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37(6):755–767. PubMed

Cadenas E, Davies KL. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000;29(3-4):222–230. PubMed

Tirosh O, Aronis A, Melendez JA. Mitochondrial state 3 to 4 respiration transition during Fas-mediated apoptosis controls cellular redox balance and rate of cell death. Biochem Pharmacol. 2003;66(8):1331–1334. PubMed

Aronis A, Melendez JA, Golan O, et al. Potentiation of Fas-mediated apoptosis by attenuated production of mitochondria-derived reactive oxygen species. Cell Death Differ. 2003;10(3):335–344. PubMed

Petrosillo G, Matera M, Casanova G, et al. Mitochondrial dysfunction in rat brain with aging Involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int. 2008;53(5):126–131. PubMed

Schönfeld P, Wojtczak L. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radic Biol Med. 2008;45(3):231–241. PubMed

Boffoli D, Scacco SC, Vergari R, et al. Decline with age of the respiratory chain activity in human skeletal muscle. Biochim Biophys Acta. 1994;1226(1):73–82. PubMed

Yin H, Zhu M. Free radical oxidation of cardiolipin: chemical mechanisms, detection and implication in apoptosis, mitochondrial dysfunction and human diseases. Free Radic Res. 2012;46(8):959–974. PubMed

Musatov A, Robinson NC. Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase. Free Radic Res. 2012;46(11):1313–1326. PubMed

Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol. 2007;292(2):C670–686. PubMed

Maes M, Fišar Z, Medina M, et al. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates-Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. 2012;20(3):127–150. PubMed

Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435(2):297–312. PubMed PMC

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