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
mitochondrialrespiratory 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
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]
^
abcdeReifschneider, 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.
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^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.
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^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.
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^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.
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abLenaz, 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.
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