Organizational and Functional Principles of the Obligate Respiratory Chain Supercomplex

ABSTRACT Proton translocating respiratory chain complexes assemble into supramolecular structures in their native cellular environment, yet the organizational principles and functional consequences of this arrangement remain incompletely understood. In Actinobacteria, the cytochrome bcc ‐ aa 3 supercomplex constitutes an obligatory respiratory unit that integrates menaquinol oxidation with dioxygen reduction and serves as a major driver of aerobic cellular respiration. Central to its architecture is the di‐heme c ‐type cytochrome subunit QcrC, which forms a continuous internal electron transfer conduit linking the Q cycle of the cytochrome bcc complex to catalysis by the cytochrome aa 3 oxidase. This direct electron transfer contrasts with the mitochondrial respiratory chain, where electron transfer between complexes III and IV relies on diffusion of soluble cytochrome c , irrespective of supercomplex formation. In this review, characteristic features of the cytochrome bcc ‐ aa 3 supercomplex are highlighted based on its cryogenic electron microscopic structure from Corynebacterium glutamicum . The latter is an actinobacterial species widely used for the industrial production of l ‐glutamic acid and l ‐lysine, and is a close homolog of pathogenic Actinobacteria which cause diphtheria and tuberculosis. Explicit descriptions of its subunit composition, overall architecture, prosthetic group arrangement, and a comparative analysis with homologous respiratory chain complexes as well as supercomplexes are provided. As Actinobacteria lack the free diffusible cytochrome c , the internal electron transfer pathway in the cytochrome bcc ‐ aa 3 supercomplex is facilitated by tight integration of the di‐heme QcrC subunit. The stable association as an obligate supercomplex is enhanced through supercomplex‐specific peripheral subunits and peripheral domains of catalytic subunits, which are discussed. Additional stabilization is provided by endogenous structural lipids, including acylated phosphatidylinositol mannosides, lipidic post‐translational modifications, and ordered cardiolipin molecules. Together with an analysis of the electrochemical properties of the catalytic subunits, these features elucidate the structural and functional principles that underlie the obligate organization of this respiratory supercomplex.