Respiratory supercomplexes and quinone channeling

Cioffi and colleagues (2022) list several functions that have been proposed for supercomplexes. These include optimization of the catalytic activity of the individual complexes and a boost to electron transfer through substrate channeling.⁷ The same list names reduced ROS generation, stabilization and assembly of Complex I, and prevention of aggregation of subunits. The authors note that some of these functions are still under debate.⁷ Fedor and Hirst (2018) argue that the channeling hypothesis has lasted because it gives a satisfying explanation for why supercomplexes exist.³ They also say the detailed kinetic and thermodynamic experiments that bear on it are not accessible to the wider community.³

Fedor and Hirst (2018) added an alternative quinol oxidase (AOX) to heart mitochondrial membranes, giving quinol a competing route of oxidation. AOX raised the rate of NADH oxidation by O2 and left membrane integrity, the supercomplexes and NADH-linked oxidative phosphorylation unaffected.¹ They concluded that quinol made by complex I is reoxidized faster outside the supercomplex than inside it. In their reading, quinone and quinol diffuse freely and channeling does not occur.² Letts and colleagues (2019) measured a rate-coupling ratio of 1.80 ± 0.05, near the 2.0 expected for perfect coupling.⁵ They concluded that their system supports a stabilizing rather than a channeling function.⁴

Brzezinski, Moe and Ädelroth (2021) point out that “supercomplex” names a phenomenon, the clustering of respiratory complexes, and not a defined assembly. They say this variation in constituents and stoichiometry has made the functional role hard to establish.⁶ Cioffi and colleagues (2022) report that the factors setting structure and stoichiometry remain unclear. They say lipid content, composition and peroxidation seem central, with cardiolipin suggested to stabilize and phosphatidylethanolamine to destabilize supercomplexes.⁸ Rao and colleagues (2026) describe Barth syndrome, in which tafazzin loss leaves mature cardiolipin deficient. They say its absence leads to disintegration of respiratory supercomplexes.⁹