线粒体氧化磷酸化的调控机制

doi:10.3969/j.issn.1673-5374.2013.04.009

摘要/Abstract

摘要：

线粒体是神经发生、突触发生、发育、突触可塑性和轴突再生的重要因子。线粒体内膜存在的氧化磷酸化是细胞功能所需的大量能量来源。ATP产物由多种机制调控，首先如氧，酶作物水平、ADP水平，线粒体膜电位，偶合率和质子漏。最近研究显示，这种调控机制正被替代，如TAC循环酶和电子传递链复形磷酸化可逆性，细胞色素C氧化酶和甲状腺粉变构抑制，脂肪酸和解偶联蛋白作用。
线粒体缺乏可以导致多种线粒体性肌病，如双相性精神障碍和精神分裂症。线粒体功能异常与其生成APT的能力有关。线粒体缺乏导致大量的活性氧释放，抗氧化能力减弱促进活性氧簇产物发生。本文将对线粒体氧化磷酸化和神经可塑性与活性氧产物的研究进行综述。

关键词: 神经再生, 线粒体, 代谢途径, 膜电位, 氧化磷酸化, 电子传递链复合物, 活性氧, 呼吸状态, 钙, 解偶联蛋白, 脂肪酸

Abstract:

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.

. 线粒体氧化磷酸化的调控机制[J]. 中国神经再生研究(英文版), 2013, 8(4): 363-375.

Jana Hroudová, Zdeněk Fišar. Control mechanisms in mitochondrial oxidative phosphorylation[J]. Neural Regeneration Research, 2013, 8(4): 363-375.

参考文献

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

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

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

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

[5] 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.

[6] Cai Q, Sheng ZH. Mitochondrial transport and docking in axons. Exp Neurol. 2009;218(2):257-267.

[7] 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.

[8] 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.

[9] Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008; 60(5):748-766.

[10] 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.

[11] Hirst J. Towards the molecular mechanism of respiratory complex I. Biochem J. 2009;425(2):327-339.

[12] 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.

[13] 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.

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

[15] 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.

[16] 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.

[17] Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552(Pt 2):335-344.

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

[19] 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.

[20] Kadenbach B. Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim Biophys Acta. 2003; 1604(2):77-94.

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

[22] 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.

[23] 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.

[24] 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.

[25] 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.

[26] 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.

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

[28] Mitchell P. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biol Rev. 1966;41:445-502.

[29] 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.

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

[31] 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.

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

[33] 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.

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

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

[36] 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.

[37] 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.

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

[39] 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.

[40] 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.

[41] 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.

[42] 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.

[43] Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31(2):139-170.

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

[45] 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.

[46] Starkov AA. "Mild" uncoupling of mitochondria. Biosci Rep. 1997;17(3):273-279.

[47] 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.

[48] 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.

[49] 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.

[50] 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.

[51] 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.

[52] 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.

[53] 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.

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

[55] 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.

[56] 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.

[57] 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.

[58] 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.

[59] 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.

[60] Je?ek P, Modrianský M, Garlid KD. Inactive fatty acids are unable to flip-flop across the lipid bilayer. FEBS Lett. 1997; 408(2):161-165.

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

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

[63] 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.

[64] 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.

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

[66] 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.

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

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

[69] 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

[70] 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.

[71] 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.

[72] 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.

[73] Beck V, Jab?rek 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.

[74] 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.

[75] 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.

[76] 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.

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

[78] Je?ek P, Jab?rek M, Garlid KD. Channel character of uncoupling protein-mediated transport. FEBS Lett. 2010; 584(10):2135-2141.

[79] 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.

[80] 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.

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

[82] Je?ek 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.

[83] 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.

[84] Tretter L, Adam-Vizi V. Generation of reactive oxygen species in the reaction catalyzed by α-ketoglutarate dehydrogenase. J Neurosci. 2004;24(36):7771-7778.

[85] Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1-13.

[86] 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.

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

[88] 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.

[89] 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.

[90] 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.

[91] 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.

[92] 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.

[93] 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.

[94] 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.

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

[96] 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.

[97] Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435(2):297-312.