Figure 1.
Architecture of the mitochondrial genome and respiratory chain.
(A) Schematic representation of the 16,569 bp human mitochondrial genome (NC_012920), with the protein-coding genes colored according to the complexes to which they contribute subunits, two ribosomal RNAs, 22 tRNAs and non-coding D-loop in white. (B) Montage depicting the structural information currently available for the five complexes that together contribute to the mitochondrial oxidative phosphorylation machinery. Each complex (to scale) is embedded in a cartoon representation of the lipid bilayer with the mitochondrial (m)-encoded subunits colored corresponding to the genome diagram. The nuclear (n)-encoded subunits are shown in grey with the relative contributions found in higher organisms detailed below.
Table 1.
Conservation of mitochondrial-encoded subunits within the complexes (I–V) between human and its high resolution structural homologs.
Figure 2.
A new structural map of human mitochondrial disease mutation sites in Complexes III and IV.
Mitochondrial diseases result in diverse pathology, and can be multi-systemic or tissue-specific. Here we show 93 individual mutation sites mapped onto their corresponding 3D crystal structures. Each mutation site is shown as a sphere colored according to the primary pathology or tissue (see legend) found to be affected in either single or groups of patients. The complete dimeric Complex IV is depicted as a ribbon model (A) with the mitochondrial-encoded subunits, MT-CO1 (B), MT-CO2 (C) and MT-CO3 (D), colored orange, yellow and green, respectively. The three COX monomers are shown separately for clarity. The dimeric Complex III is shown in the same format (E) with the mitochondrial-encoded MT-CYB (F) subunits colored as blue ribbons.
Table 2.
Structural classification and pathogenic prediction of mutations in the mtDNA complex III and IV genes (mt-cyb and mt-co1-3, respectively) reported with known human disease associations and biochemical effects.
Table 3.
Structural classification and pathogenic prediction of mutations in the mtDNA complex III and IV genes (mt-cyb and mt-co1-3, respectively) reported with human disease associations but without known biochemical effects.
Figure 3.
(A) The active site region of the wild-type MT-CO1 subunit of complex IV is depicted as a ribbon diagram with key amino acids as orange stick representations (within red circles). The heme a3 is colored in green with the Fe atom in grey. (B) Two separate mutations have been modeled, I280T and V380I. More detailed diagrams can be found in Figure S5.
Figure 4.
The role of residues contributing to substrate-binding cavities.
MT-CYB has several deep pockets for binding, redox interaction and modification of substrates. (A) The Qi site is formed by the contribution of multiple helical regions (blue) that fold around heme bH (green) while maintaining contact with the solvent. The wild-type residue N32 (PDB 1NTZ) is shown making hydrogen bonds (dotted lines) with the natural substrate ubiquinone (orange), within the same pocket. (B) Mutation to S32 results in the loss of key hydrogen bonds previously identified to be crucial in the redox mechanism.
Figure 5.
Assembly disruption from bigenomic protein incompatibility in Complex IV.
(A) The mitochondrial subunits are surrounded by nuclear-encoded subunits that make intimate interactions, in this case MT-CO2 (yellow ribbons) with COX6C (purple ribbon), respectively. The wild type M29 residue is shown in stick form occupying a position between to aromatic side chains from COX6C. (B) The mutation K29 results in the incorporation of a long and polar side chain that is incompatible within the tight interface between MT-CO2 and COX6C. (C) The wild type-enzyme is shown as a surface model in the same color scheme with the position of the mutation site highlighted by a dotted red circle. (D) A surface illustration depicts the position of the K29 mutation and the potential resulting aberrant assembly of the nuclear subunit COX6C.