The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I

Abstract

Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI’s accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI’s 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.

Structural insights into the assembly and the function of the plant oxidative phosphorylation system

“…2). Further detail on CI subunits, nomenclature equivalencies, and comparison across lineages can be found elsewhere (Senkler et al ., 2017a; Maldonado et al ., 2020; Soufari et al ., 2020; Klusch et al ., 2021; Padavannil et al ., 2022).…”

“…NDUA12 is then stabilized by NDUS6, whose N-terminal domain extends above NDUA12. This structural organization defines the assembly sequence and is part of an important checkpoint in the assembly pathway in opisthokonts (Parey et al, 2019;Padavannil et al, 2022) (Fig. 4).…”

Structures of Tetrahymena ’s respiratory chain reveal the diversity of eukaryotic core metabolism

“…Although the catalytic mechanisms of the individual mETC complexes are likely conserved across species, some structural differences have been observed between model organisms. Each mETC complex can be split into core subunits, which are essential for catalysis and are conserved from the bacterial homologs, and accessory subunits, which are important for the assembly and activity of the complexes but are not universally conserved ( 10 , 11 ). CI is composed of 14 core subunits, arranged into two “arms” of an “L”-shape, universally conserved in the model eukaryotes with known structures, covering the Opisthokont [fungi ( 12 ) and metazoan ( 13 )] and Archaeplastida [red/green algae and plants ( 14 – 16 )] clades.…”

Human induced pluripotent stem cells for studying mitochondrial diseases in the heart

“…Of these, CI is the largest and most elaborate, containing 45 subunits amounting to a total mass of ∼ 1 MDa. Mutations to the 13 ‘core’ protein subunits or the 31 accessory subunits account for nearly one‐third of ETC deficiencies such as Leber's hereditary optic neuropathy, Leigh syndrome and mitochondrial encephalomyopathy [71].…”