Cryo-EM structure of the respirasome and supercomplex architecture

Blue native gel electrophoresis was developed in the 1990s. Caruana and Stroud (2020) report that it revealed very large assemblies of 1.5 to 2 MDa, containing various arrangements of Complexes I, III and IV.⁴ The form with one Complex I, a Complex III dimer and one Complex IV is typically the most abundant. They therefore treat it as the base functional unit, the respirasome.⁴ They add that supercomplexes were at first criticised as artefacts of analysis.⁴ Parodi-Rullán and colleagues (2019) likewise describe the respirasome as the main respiratory chain supercomplex, with complexes I, III and IV in various stoichiometries.³

Caruana and Stroud (2020) say the first supercomplex structure in atomic detail was the ovine respirasome, in 2016.⁵ Sazanov and co-workers gave loose and tight forms, plus the CI/III2 supercomplex. Porcine structures followed from the Yang group, and a bovine structure from Kühlbrandt and co-workers.⁵ Sousa, Mills, Vonck and Kühlbrandt (2016) deposited the bovine model as 5LUF.¹ In every respirasome the Complex I membrane arm curves around the Complex III dimer.⁶ The porcine maps have higher resolution, 4 Å against 5.8 Å for the ovine and 9 Å for the bovine. Caruana and Stroud note that the porcine models have problems in assigning subunits and cofactors.⁷

Letts, Fiedorczuk, Degliesposti, Skehel and Sazanov (2019) found that the relative orientation between the two arms of Complex I, and between Complex I and the Complex III dimer, was variable. This gave lower resolution at the edges of those regions.² They therefore refined the peripheral arm, the membrane arm and the Complex III dimer separately. They also found a small class of particles lacking the NADH-binding N-module.² Caruana and Stroud report that no structure revealed new subunits specific to the supercomplex.⁶ Protasoni and Zeviani (2021) cite estimates that in humans 85% to 100% of Complex I sits in supercomplexes, against 55% to 65% of Complex III and 15% to 25% of Complex IV.⁹

Parodi-Rullán and colleagues (2019) report the proposal that the respirasome facilitates electron transfer and reduces electron leakage and mitochondrial ROS production.³ Caruana and Stroud (2020) list the same kind of roles: channelling of CoQ and cytochrome c, stability and protection from ROS. They call substrate channelling arguably the most often cited of the proposed functions. They also state that the concept is disputed on both structural and biochemical evidence.⁸ Caruana and Stroud report that the channelling concept is disputed.