Respirasoma

In 1955, biologists Britton Chance and G.R. Williams first put forward the idea that respiratory enzymes assemble into larger complexes ^[10] , although the free-fluid model of the organization of the respiratory chain still remained basic and was considered standard. However, already in 1985, researchers began to isolate the supercomplex of complexes III / IV from bacteria ^{[11] [12] [13]} and yeast ^{[14] [15]} . Finally, in 2000, Hermann Shegger and Katie Pfeiffer, using gel electrophoresis with Coomassie , isolated individual bovine respiratory complexes, showing that complexes I, III, and IV form a supercomplex ^[16] .

After the desired respirasomes were isolated, there was still the possibility that the resulting complexes formed exclusively in vitro and were simply an artifact of isolation. After several years of unsuccessful attempts to prove or disprove the existence of respirases using various methods of protein isolation, Lapuent-Brun et al. decided to use a different approach. Since it was obvious that if respirasomes really exist, then some auxiliary protein should be used to combine the respiratory complexes into one supercomplex. It turned out that one protein under the name Cox7a2l ( English cytochrome c oxidase subunit VIIa polypeptide 2-like ) is present only in supercomplexes containing the respiratory complex IV (respirasomes and supercomplex III + IV) and never occurs in single complexes. Researchers were fortunate enough to accidentally discover that in three mutant mouse cell lines with a damaged form of this protein, supercomplexes involving complex IV cannot be detected in the mitochondrial membrane. Moreover, if a normal protein gene is inserted into mutant cells, then these supercomplexes begin to form in them. From all this, the researchers made a logical conclusion: this protein helps complex IV to form supercomplexes and therefore deserves to be renamed into the factor of combining supercomplexes I ( English supercomplex assembly factor I , or SCAFI) ^[17] .

Similar proteins, Rcf1 and Rcf2, stabilizing supercomplexes were found in yeast ^[18] .

The most common supercomplexes are complex I / III, complex I / III / IV and complex III / IV. Most of the molecules of complex II in both plant and animal mitochondria are in free form. ATP synthase can also migrate together with other supercomplexes in the form of a dimer, but it is hardly a part of them ^[1] .

The formation of a super complex is apparently a dynamic process. Respiratory complexes can alternate participation in respirasomes and existence in a free state. It is not known what triggers the process of organizing respiratory enzymes into supercomplexes, but studies have shown that their formation largely depends on the lipid composition of mitochondrial membranes, and in particular requires cardiolipin ^[19] . In yeast mitochondria, the content of cardiolipin was reduced, and the number detected by respiras was significantly lower than in other organisms ^{[19] [20]} . According to Wentz et al. (2009), cardiolipin stabilizes the formation of respirases by neutralizing the charges of lysine residues during the interaction of the complex III domain and complex IV ^[21] . In 2012, Bazan et al. it was possible in vitro to obtain trimeric and tetrameric supercomplexes of composition III ₂ IV ₁ and III ₂ IV ₂ from purified complexes III and IV of Saccharomyces cerevisiae by adding liposomes with cardiolipin to them ^[22] .

Another hypothesis is that rispirasomes can form under the influence of the membrane potential , which leads to changes in electrostatic and hydrophobic interactions, which mediates the assembly or disassembly of supercomplexes ^[23] .

According to some reports, respirasomes may not be the highest form of respiratory complex organization. Based on electron microscopy data, as well as on the fact that IV complexes of bull mitochondria are capable of forming tetramers under certain conditions, a hypothesis has been put forward about megacomplexes consisting of respires or other respiratory “chains”. According to this model, the basis of this chain is a single dimer of complex III (III ₂ ), surrounded on both sides by two IV complexes. These structural units are connected through dimerization of complexes IV, as a result of which a thread of type IV-IV-III ₂ -IV-IV-III ₂ should be formed, which is tightly surrounded on the sides by complexes I. The structural unit of such a thread should be a supercomplex of composition I ₁ III ₂ IV ^[24] .

The functional purpose of the respiras is not entirely clear, but recent studies shed light on their purpose. It has been hypothesized that the organization of respiratory enzymes into supercomplexes reduces oxidative damage and improves metabolic efficiency. Schaefer et al. (2006) demonstrated that supercomplexes which contain complex IV, the activity of complexes I and III was higher. This indicates that complex IV in some way changes the conformation of other complexes, which leads to an increase in their catalytic activity ^[25] . Gradually, evidence began to accumulate that the presence of respiras is necessary for the stability and functioning of complex I, which in the absence of complexes III or IV is practically unstable. Thus, it has been shown on mutant human cells that complex I is necessary for the formation of complex III, and, on the other hand, the absence of complex III leads to the loss of complex I. In addition, a number of studies on animal cells provide evidence that for the stability of complex I complexes IV and a dimer of complex III are required.

In 2013, Lapuenta-Brun et al. demonstrated that the assembly of supercomplexes "dynamically organizes the flow of electrons to optimize the use of existing substrates." The presence of respires makes the system more branched and flexible, which makes it possible to simultaneously oxidize several substrates simultaneously ( succinate and pyruvate + malate ), but if only succinate enters the mitochondria, which transfers electrons to the transport via FAD , then its oxidation proceeds faster in the absence of respiras ^[17] .

• The presence of supercomplexes in the respiratory chain of electron transfer is provided by SCAFI protein
• Respiratory supercomplexes of plant mitochondria: structure and possible functions