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Hirst 2018 BMC Biol

From Bioblast
Publications in the MiPMap
Hirst J (2018) Open questions: respiratory chain supercomplexes-why are they there and what do they do?. BMC Biol 16:111.

» PMID:30382836 Open Access

Hirst J (2018) BMC Biol

Abstract: In the mitochondrial inner membrane the respiratory enzymes associate to form supramolecular assemblies known as supercomplexes. The existence of supercomplexes is now widely accepted-but what functional or structural advantages, if any, do they confer?


Labels: MiParea: mt-Membrane 



Enzyme: Supercomplex 




Selected quotes

  • Importantly, it is a long way (~ 100 Å; Fig. 1) from the exit to the complex I Q-binding channel to the closest complex III QH2-binding site, and there is no confining protein structure between the two sites to guide diffusion. Similarly, the structures reveal no barriers to the free diffusion of cytochrome c between complexes III and IV. Therefore, no physical channels exist and the term ‘substrate channelling’ is inappropriate. In the case of true substrate channelling, typically to prevent a toxic intermediate from escaping into the cellular environment, substrates are contained as they move between sites to prevent them exchanging with substrates outside [5]. Although channels may also decrease the transit time between sites, they represent a higher level of organisation for this purpose than simply placing the sites in close proximity to one another—as occurs in the respirasome, as well as in any tightly packed environment.
  • Indeed, a strict channelling regime, with a tiny pool of Q/QH2 and cytochrome c trapped inside each supercomplex would prevent redox sensing through the status of the membrane pool and comprise the ability of the system to withstand the dysfunction of individual complexes.
  • The local environments of the buried enzyme active sites, at which O2 reacts to generate superoxide, are structurally defined sites that are distant from the contact points and interfaces between the complexes. Superoxide production is determined by the levels of reactive intermediates present at those sites (determined in turn by the mechanism and environmental parameters such as substrate concentrations) and by the access of O2 to the sites. The latter may be hindered by the adjacent complexes in the supercomplex, but similarly by any complex in the vicinity (by the packing density)—and furthermore, the flavin site of complex I (where NADH is oxidised), which is an important site of superoxide production by the respiratory chain, is exposed outside the supercomplex, atthe top of the enzyme’s hydrophilic arm.
  • Supercomplexes have also been proposed to stabilise the individual complexes, or to provide a scaffold for their assembly. Mutations in the individual complexes often affect the levels of complexes and supercomplexes present, but in particular, mutations that cause defects in complexes III and IV often lead to defects in complex I also [9]. The combined defect suggests a communication between the complexes which could be mediated by the supercomplex structure. However, a supercomplex-independent mechanism also exists to explain the effect: deficiencies in the rate of respiratory-chain catalysis cause the NAD+/NADH, fumarate/succinate and Q/QH2 pools to become more reduced, and reactive oxygen species production from complex I to increase—and complex I is susceptible to oxidative damage.
  • Instead, I contend that supercomplexes represent a physical adaptation of the respiratory system to its environment. The mitochondrial inner membrane is an extremely protein-dense environment. As loosely associated but closely packed assemblies, supercomplexes offer a favourable way to allow more complexes to be crammed into the membrane, while avoiding the unfavourable and irreversible interactions that may lead to protein aggregation or degradation.
  • ...in mammalian mitochondria, the respiratory supercomplexes occupy the planar cristae surface....supercomplexes enforce a homogeneous mixture and distribution of the complexes in the membrane. Within the close-packed homogeneous mixture, the distances that Q/QH2 and cytochrome c must diffuse between enzymes is minimised—but with no constraint on them to react with their specific partners in the same supercomplex. Therefore, supercomplexes may be instrumental for the stability of the densely and homogeneously packed planar cristae membrane—by supporting this membrane environment they promote the efficient and rapid catalysis of respiration.