The road to the structure of the mitochondrial respiratory chain supercomplex

Abstract

The four complexes of the mitochondrial respiratory chain are critical for ATP production in most eukaryotic cells. Structural characterisation of these complexes has been critical for understanding the mechanisms underpinning their function. The three proton-pumping complexes, Complexes I, III and IV associate to form stable supercomplexes or respirasomes, the most abundant form containing 80 subunits in mammals. Multiple functions have been proposed for the supercomplexes, including enhancing the diffusion of electron carriers, providing stability for the complexes and protection against reactive oxygen species. Although high-resolution structures for Complexes III and IV were determined by X-ray crystallography in the 1990s, the size of Complex I and the supercomplexes necessitated advances in sample preparation and the development of cryo-electron microscopy techniques. We now enjoy structures for these beautiful complexes isolated from multiple organisms and in multiple states and together they provide important insights into respiratory chain function and the role of the supercomplex. While we as non-structural biologists use these structures for interpreting our own functional data, we need to remind ourselves that they stand on the shoulders of a large body of previous structural studies, many of which are still appropriate for use in understanding our results. In this mini-review, we discuss the history of respiratory chain structural biology studies leading to the structures of the mammalian supercomplexes and beyond.

Keywords: mitochondria; oxidative phosphorylation; structural biology.

Figure 1.. Timeline for the identification of key structures for each of the three respiratory chain complexes present in the supercomplex.

Structures solved using X-ray crystallography are coloured by yellow nodes, with Cryo-EM structures coloured by orange nodes. Structures which had low-quality density maps (PDB:1QCR and 5XTI) or only existing as an alpha-helical model (membrane region of PDB:3M9S) are depicted using the surface representation, whereas high-resolution structures are shown using the ribbon representation. Note: the CI₂/CIII₂/CIV₂ megacomplex structure is a top view, whereas other structures are shown as side views.