Complex I is a very large enzyme catalyzing the first step of the mitochondrial electron transport chain. The enzyme oxidizes NADH transferring electrons to Ubiquinone (Coenzyme Q, CoQ), a lipid soluble electron carrier embedded in the lipid bilayer of the inner mitochondrial membrane. The total number of subunits in the bovine enzyme is 46 for a molecular mass of about 1000 kDa. Seven subunits are the products of the mitochondrial genome, and correspond to hydrophobic components named ND1–ND6 and ND4L. The minimal active form of the enzyme is that found in bacteria, composed of 14 subunits, all of which are homologous to their mitochondrial counterparts, while all other subunits are called “accessory subunits” and their role in the mitochondrial enzyme is not clear. From structural and phylogenetic considerations, the enzyme is envisaged to consist of three different sectors: a dehydrogenase unit and a hydrogenase-like unit constituting the peripheral arm protruding into the matrix, and a transporter unit deeply embedded in the membrane.
The enzyme is endowed with several prosthetic groups: FMN is the entry point for electrons from NADH, that are then transferred to the iron–sulphur clusters. Enzymes from different sources have different numbers of iron–sulphur clusters, most of which share the same midpoint potential and are called “isopotential” clusters. Two clusters present different characteristics: N1a, that is of the kind Fe2S2, has the lowest midpoint potential (Em = −370 mV) and N2, that is of the kind Fe4S4, resides at the interface between the 22 kDa subunit PSST and the 49 kDa subunits and has the highest midpoint potential (Em between −150 mV and −50 mV), presenting EPR magnetic interactions with the ubisemiquinone radicals; for these reasons, it is considered to be the direct electron donor to ubiquinone. N2 iron–sulphur cluster is most likely located in the connection between the peripheral and the membrane arm.
