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. Respirasome Dudkina 2011.gif
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]

Contents

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Cytochrome</span> Redox-active proteins containing a heme with a Fe atom as a cofactor

Cytochromes are redox-active proteins containing a heme, with a central iron (Fe) atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of binding. Four varieties are recognized by the International Union of Biochemistry and Molecular Biology (IUBMB), cytochromes a, cytochromes b, cytochromes c and cytochrome d.

<span class="mw-page-title-main">Oxidative phosphorylation</span> Metabolic pathway

Oxidative phosphorylation or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP). In eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy than alternative fermentation processes such as anaerobic glycolysis.

<span class="mw-page-title-main">Electron transport chain</span> Energy-producing metabolic pathway

An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. The electrons that are transferred from NADH and FADH2 to the ETC involves four multi-subunit large enzymes complexes and two mobile electron carriers. Many of the enzymes in the electron transport chain are embedded within the membrane.

<span class="mw-page-title-main">Cytochrome c</span> Protein-coding gene in the species Homo sapiens

The cytochrome complex, or cyt c, is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. It transfers electrons between Complexes III and IV. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis. In humans, cytochrome c is encoded by the CYCS gene.

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.

<span class="mw-page-title-main">Coenzyme Q – cytochrome c reductase</span> Class of enzymes

The coenzyme Q : cytochrome c – oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain, playing a critical role in biochemical generation of ATP. Complex III is a multisubunit transmembrane protein encoded by both the mitochondrial and the nuclear genomes. Complex III is present in the mitochondria of all animals and all aerobic eukaryotes and the inner membranes of most eubacteria. Mutations in Complex III cause exercise intolerance as well as multisystem disorders. The bc1 complex contains 11 subunits, 3 respiratory subunits, 2 core proteins and 6 low-molecular weight proteins.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Succinate dehydrogenase</span> Enzyme

Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates in both the citric acid cycle and the electron transport chain. Histochemical analysis showing high succinate dehydrogenase in muscle demonstrates high mitochondrial content and high oxidative potential.

Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most bacteria. The name "cardiolipin" is derived from the fact that it was first found in animal hearts. It was first isolated from the beef heart in the early 1940s by Mary C. Pangborn. In mammalian cells, but also in plant cells, cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane, where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism.

<span class="mw-page-title-main">Rieske protein</span> Protein family with an iron–sulfur center transferring electrons

Rieske proteins are iron–sulfur protein (ISP) components of cytochrome bc1 complexes and cytochrome b6f complexes and are responsible for electron transfer in some biological systems. John S. Rieske and co-workers first discovered the protein and in 1964 isolated an acetylated form of the bovine mitochondrial protein. In 1979 Trumpower's lab isolated the "oxidation factor" from bovine mitochondria and showed it was a reconstitutively-active form of the Rieske iron-sulfur protein
It is a unique [2Fe-2S] cluster in that one of the two Fe atoms is coordinated by two histidine residues rather than two cysteine residues. They have since been found in plants, animals, and bacteria with widely ranging electron reduction potentials from -150 to +400 mV.

<span class="mw-page-title-main">Inner mitochondrial membrane</span>

The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.

<span class="mw-page-title-main">Mitochondrial trifunctional protein</span>

Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">Alternative oxidase</span>

The alternative oxidase (AOX) is an enzyme that forms part of the electron transport chain in mitochondria of different organisms. Proteins homologous to the mitochondrial oxidase and the related plastid terminal oxidase have also been identified in bacterial genomes.

<span class="mw-page-title-main">Ubiquinol</span> Chemical compound

A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.

<span class="mw-page-title-main">CYC1</span> Protein-coding gene in the species Homo sapiens

Cytochrome c1, heme protein, mitochondrial (CYC1), also known as UQCR4, MC3DN6, Complex III subunit 4, Cytochrome b-c1 complex subunit 4, or Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit is a protein that in humans is encoded by the CYC1 gene. CYC1 is a respiratory subunit of Ubiquinol Cytochrome c Reductase, which is located in the inner mitochondrial membrane and is part of the electron transport chain. Mutations in this gene may cause mitochondrial complex III deficiency, nuclear, type 6.

<span class="mw-page-title-main">SCO1</span> Protein-coding gene in the species Homo sapiens

Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene. SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. The expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase deficiency.

Monolysocardiolipin (MLCL) is a phospholipid with three fatty acid chains located in the inner membrane of mitochondria.

<span class="mw-page-title-main">COX5A</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

<span class="mw-page-title-main">COA3</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.

References

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  2. 1 2 3 4 5 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.
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  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.
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  17. 1 2 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. 1 2 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.
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  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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