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Supercomplex

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I/III/IV Supercomplex. Complex I in yellow, Complex III in green, and Complex IV in purple. A, B, and E are side views of the complexes as they are oriented upright in the membrane. Horizontal lines on E indicate the position of the membrane. D is a view from the intermembrane space. C and F are viewed from inside the matrix.

Modern biological research has revealed strong evidence that the enzymes of the mitochondrial respiratory chain assemble into larger, supramolecular structures called supercomplexes, instead of the traditional fluid model of discrete enzymes dispersed in the inner mitochondrial membrane. These supercomplexes are functionally active and necessary for forming stable respiratory complexes.[1]

One supercomplex of complex I, III, and IV make up a unit known as a respirasome. Respirasomes have been found in a variety of species and tissues, including rat brain,[2] liver,[2] kidney,[2] skeletal muscle,[2][3] heart,[2] bovine heart,[4] human skin fibroblasts,[5] fungi,[6] plants,[7][8] and C. elegans.[9]

History

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In 1955, biologists Britton Chance and G. R. Williams were the first to propose the idea that respiratory enzymes assemble into larger complexes,[10] although the fluid state model remained the standard. However, as early as 1985, researchers had begun isolating complex III/complex IV supercomplexes from bacteria[11][12][13] and yeast.[14][15] Finally, in 2000 Hermann Schägger and Kathy Pfeiffer used Blue Native PAGE to isolate bovine mitochondrial membrane proteins, showing Complex I, III, and IV arranged in supercomplexes.[16]

Composition and formation

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The most common supercomplexes observed are Complex I/III, Complex I/III/IV, and Complex III/IV. Most of Complex II is found in a free-floating form in both plant and animal mitochondria. Complex V can be found co-migrating as a dimer with other supercomplexes, but scarcely as part of the supercomplex unit.[1]

Supercomplex assembly appears to be dynamic and respiratory enzymes are able to alternate between participating in large respirasomes and existing in a free state. It is not known what triggers changes in complex assembly, but research has revealed that the formation of supercomplexes is heavily dependent upon the lipid composition of the mitochondrial membrane, and in particular requires the presence of cardiolipin, a unique mitochondrial lipid.[17] In yeast mitochondria lacking cardiolipin, the number of enzymes forming respiratory supercomplexes was significantly reduced.[17][18] According to Wenz et al. (2009), cardiolipin stabilizes the supercomplex formation by neutralizing the charges of lysine residues in the interaction domain of Complex III with Complex IV.[19] In 2012, Bazan et al. was able to reconstitute trimer and tetramer Complex III/IV supercomplexes from purified complexes isolated from Saccharomyces cerevisiae and exogenous cardiolipin liposomes.[20]

Another hypothesis for respirasome formation is that membrane potential may initiate changes in the electrostatic/hydrophobic interactions mediating the assembly/disassembly of supercomplexes.[21]

Functional significance

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The functional significance of respirasomes is not entirely clear but more recent research is beginning to shed some light on their purpose. It has been hypothesized that the organization of respiratory enzymes into supercomplexes reduces oxidative damage and increases metabolism efficiency. Schäfer et al. (2006) demonstrated that supercomplexes comprising Complex IV had higher activities in Complex I and III, indicating that the presence of Complex IV modifies the conformation of the other complexes to enhance catalytic activity.[22] Evidence has also been accumulated to show that the presence of respirasomes is necessary for the stability and function of Complex I.[21] In 2013, Lapuente-Brun et al. demonstrated that supercomplex assembly is "dynamic and organizes electron flux to optimize the use of available substrates."[23]

References

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  1. ^ a b Vartak, Rasika; Porras, Christina Ann-Marie; Bai, Yidong (2013). "Respiratory supercomplexes: structure, function and assembly". Protein & Cell. 4 (8): 582–590. doi:10.1007/s13238-013-3032-y. ISSN 1674-800X. PMC 4708086. PMID 23828195.
  2. ^ a b c d e Reifschneider, Nicole H.; Goto, Sataro; Nakamoto, Hideko; Takahashi, Ryoya; Sugawa, Michiru; Dencher, Norbert A.; Krause, Frank (2006). "Defining the Mitochondrial Proteomes from Five Rat Organs in a Physiologically Significant Context Using 2D Blue-Native/SDS-PAGE". Journal of Proteome Research. 5 (5): 1117–1132. doi:10.1021/pr0504440. ISSN 1535-3893. PMID 16674101.
  3. ^ Lombardi, A.; Silvestri, E.; Cioffi, F.; Senese, R.; Lanni, A.; Goglia, F.; de Lange, P.; Moreno, M. (2009). "Defining the transcriptomic and proteomic profiles of rat ageing skeletal muscle by the use of a cDNA array, 2D- and Blue native-PAGE approach". Journal of Proteomics. 72 (4): 708–721. doi:10.1016/j.jprot.2009.02.007. ISSN 1874-3919. PMID 19268720.
  4. ^ Schäfer, Eva; Dencher, Norbert A.; Vonck, Janet; Parcej, David N. (2007). "Three-Dimensional Structure of the Respiratory Chain Supercomplex I1III2IV1from Bovine Heart Mitochondria†,‡". Biochemistry. 46 (44): 12579–12585. doi:10.1021/bi700983h. ISSN 0006-2960. PMID 17927210.
  5. ^ Rodríguez-Hernández, Ángeles; Cordero, Mario D.; Salviati, Leonardo; Artuch, Rafael; Pineda, Mercé; Briones, Paz; Gómez Izquierdo, Lourdes; Cotán, David; Navas, Plácido; Sánchez-Alcázar, José A. (2009). "Coenzyme Q deficiency triggers mitochondria degradation by mitophagy". Autophagy. 5 (1): 19–33. doi:10.4161/auto.5.1.7174. hdl:10261/40287. ISSN 1554-8627. PMID 19115482.
  6. ^ Krause, F. (2006). "OXPHOS Supercomplexes: Respiration and Life-Span Control in the Aging Model Podospora anserina". Annals of the New York Academy of Sciences. 1067 (1): 106–115. Bibcode:2006NYASA1067..106K. doi:10.1196/annals.1354.013. ISSN 0077-8923. PMID 16803975. S2CID 9939670.
  7. ^ Eubel, Holger; Heinemeyer, Jesco; Sunderhaus, Stephanie; Braun, Hans-Peter (2004). "Respiratory chain supercomplexes in plant mitochondria". Plant Physiology and Biochemistry. 42 (12): 937–942. doi:10.1016/j.plaphy.2004.09.010. ISSN 0981-9428. PMID 15707832.
  8. ^ Sunderhaus, Stephanie; Klodmann, Jennifer; Lenz, Christof; Braun, Hans-Peter (2010). "Supramolecular structure of the OXPHOS system in highly thermogenic tissue of Arum maculatum". Plant Physiology and Biochemistry. 48 (4): 265–272. doi:10.1016/j.plaphy.2010.01.010. ISSN 0981-9428. PMID 20144873.
  9. ^ Suthammarak, Wichit; Somerlot, Benjamin H.; Opheim, Elyce; Sedensky, Margaret; Morgan, Philip G. (2013). "Novel interactions between mitochondrial superoxide dismutases and the electron transport chain". Aging Cell. 12 (6): 1132–1140. doi:10.1111/acel.12144. ISSN 1474-9718. PMC 3838459. PMID 23895727.
  10. ^ Chance, Britton; Williams, G. R. (1955). "A Method for the Localization of Sites for Oxidative Phosphorylation". Nature. 176 (4475): 250–254. Bibcode:1955Natur.176..250C. doi:10.1038/176250a0. ISSN 0028-0836. PMID 13244669. S2CID 4184316.
  11. ^ E. A. Berry & B. L. Trumpower (February 1985). "Isolation of ubiquinol oxidase from Paracoccus denitrificans and resolution into cytochrome bc1 and cytochrome c-aa3 complexes". The Journal of Biological Chemistry. 260 (4): 2458–2467. doi:10.1016/S0021-9258(18)89576-X. PMID 2982819.
  12. ^ T. Iwasaki, K. Matsuura & T. Oshima (December 1995). "Resolution of the aerobic respiratory system of the thermoacidophilic archaeon, Sulfolobus sp. strain 7. I. The archaeal terminal oxidase supercomplex is a functional fusion of respiratory complexes III and IV with no c-type cytochromes". The Journal of Biological Chemistry. 270 (52): 30881–30892. doi:10.1074/jbc.270.52.30881. PMID 8537342.
  13. ^ N. Sone, M. Sekimachi & E. Kutoh (November 1987). "Identification and properties of a quinol oxidase super-complex composed of a bc1 complex and cytochrome oxidase in the thermophilic bacterium PS3". The Journal of Biological Chemistry. 262 (32): 15386–15391. doi:10.1016/S0021-9258(18)47736-8. PMID 2824457.
  14. ^ H. Boumans, L. A. Grivell & J. A. Berden (February 1998). "The respiratory chain in yeast behaves as a single functional unit". The Journal of Biological Chemistry. 273 (9): 4872–4877. doi:10.1074/jbc.273.9.4872. PMID 9478928.
  15. ^ C. Bruel, R. Brasseur & B. L. Trumpower (February 1996). "Subunit 8 of the Saccharomyces cerevisiae cytochrome bc1 complex interacts with succinate-ubiquinone reductase complex". Journal of Bioenergetics and Biomembranes. 28 (1): 59–68. doi:10.1007/bf02109904. PMID 8786239. S2CID 23909319.
  16. ^ H. Schagger & K. Pfeiffer (April 2000). "Supercomplexes in the respiratory chains of yeast and mammalian mitochondria". The EMBO Journal. 19 (8): 1777–1783. doi:10.1093/emboj/19.8.1777. PMC 302020. PMID 10775262.
  17. ^ a b Zhang, M. (2002). "Gluing the Respiratory Chain Together. CARDIOLIPIN IS REQUIRED FOR SUPERCOMPLEX FORMATION IN THE INNER MITOCHONDRIAL MEMBRANE". Journal of Biological Chemistry. 277 (46): 43553–43556. doi:10.1074/jbc.C200551200. ISSN 0021-9258. PMID 12364341.
  18. ^ Zhang, M. (2005). "Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria". Journal of Biological Chemistry. 280 (33): 29403–29408. doi:10.1074/jbc.M504955200. ISSN 0021-9258. PMC 4113954. PMID 15972817.
  19. ^ Wenz, Tina; Hielscher, Ruth; Hellwig, Petra; Schägger, Hermann; Richers, Sebastian; Hunte, Carola (2009). "Role of phospholipids in respiratory cytochrome bc1 complex catalysis and supercomplex formation". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1787 (6): 609–616. doi:10.1016/j.bbabio.2009.02.012. ISSN 0005-2728. PMID 19254687.
  20. ^ Bazan, S.; Mileykovskaya, E.; Mallampalli, V. K. P. S.; Heacock, P.; Sparagna, G. C.; Dowhan, W. (2012). "Cardiolipin-dependent Reconstitution of Respiratory Supercomplexes from Purified Saccharomyces cerevisiae Complexes III and IV". Journal of Biological Chemistry. 288 (1): 401–411. doi:10.1074/jbc.M112.425876. ISSN 0021-9258. PMC 3537037. PMID 23172229.
  21. ^ a b Lenaz, Giorgio; Genova, Maria Luisa (2012). "Supramolecular Organisation of the Mitochondrial Respiratory Chain: A New Challenge for the Mechanism and Control of Oxidative Phosphorylation". Mitochondrial Oxidative Phosphorylation. Advances in Experimental Medicine and Biology. Vol. 748. pp. 107–144. doi:10.1007/978-1-4614-3573-0_5. ISBN 978-1-4614-3572-3. ISSN 0065-2598. PMID 22729856.
  22. ^ Schafer, E. (2006). "Architecture of Active Mammalian Respiratory Chain Supercomplexes". Journal of Biological Chemistry. 281 (22): 15370–15375. doi:10.1074/jbc.M513525200. ISSN 0021-9258. PMID 16551638.
  23. ^ Lapuente-Brun, E.; Moreno-Loshuertos, R.; Acin-Perez, R.; Latorre-Pellicer, A.; Colas, C.; Balsa, E.; Perales-Clemente, E.; Quiros, P. M.; Calvo, E.; Rodriguez-Hernandez, M. A.; Navas, P.; Cruz, R.; Carracedo, A.; Lopez-Otin, C.; Perez-Martos, A.; Fernandez-Silva, P.; Fernandez-Vizarra, E.; Enriquez, J. A. (2013). "Supercomplex Assembly Determines Electron Flux in the Mitochondrial Electron Transport Chain". Science. 340 (6140): 1567–1570. Bibcode:2013Sci...340.1567L. doi:10.1126/science.1230381. hdl:10261/129138. ISSN 0036-8075. PMID 23812712. S2CID 206545337.
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