ATP Synthase Diseases of Mitochondrial Genetic Origin

Abstract

Devastating human neuromuscular disorders have been associated to defects in the ATP synthase. This enzyme is found in the inner mitochondrial membrane and catalyzes the last step in oxidative phosphorylation, which provides aerobic eukaryotes with ATP. With the advent of structures of complete ATP synthases, and the availability of genetically approachable systems such as the yeast Saccharomyces cerevisiae, we can begin to understand these molecular machines and their associated defects at the molecular level. In this review, we describe what is known about the clinical syndromes induced by 58 different mutations found in the mitochondrial genes encoding membrane subunits 8 and a of ATP synthase, and evaluate their functional consequences with respect to recently described cryo-EM structures.

Keywords: F1Fo ATP synthase structure; MT-ATP6; MT-ATP8; mitochondrial DNA (mtDNA); mitochondrial diseases.

Figure 1

Cartoon representation of the yeast F₁F_o ATP synthase. The view is horizontally to the membrane shown in grayscale. The structure was drawn according to (Hahn et al., , PDB code 5FL7). For simplicity the structure is shown without subunits e, f, g, I, and a truncated subunit b. The figure was made in Pymol (The PyMOL Molecular Graphics System, Version 0.99, Schrödinger, LLC), using the following color code: α, forest; β, split pea; γ, density; δ, cyan; ε, white; OSCP, red; b (= 4 in yeast), dirty violet; d, orange; h, salmon; 8, green; a, blue; c-ring, yellow. The arrows indicate the path of protons (see also Figure 4) and nucleotide conversion. For details see text.

Figure 2

ATP6 and ATP8 genes and sites of pathogenic mutations. The two coding sequences overlap, between positions 8527 and 8572 (cyan) of the human mitochondrial genome. Start and end nucleotide numbers are indicated. The number of mutations (m) identified in patients and their positions are indicated. These mutations are listed in Table 2.

Figure 3

Sequence alignment of subunits a, b and 8 from a selected range of species. (A) Alignment of bacterial subunits b (b′ or b2 isoform) and mitochondrial subunits 8. The sequences of subunit b are from Rhodobacter sphaeroides (R.s.), Ruegeria sp. (R.sp), Roseobacter denitrificans (R.d.), Jannaschia sp. (J.sp) and Dinoroseobacter shibae (D.s.). The length of N- and C-termini extensions are given. The sequences of subunit 8 are from a selection of mammals and the yeast species Schizosaccharomyces pombe (S.p.), Podospora anserina (P.a.), Yarrowia lipolytica (Y.l.), Saccharomyces cerevisiae (S.c.) and Candida glabrata (C.g.). (B) Alignment of subunit a. Homo sapiens (H.s.), Bos taurus (B.t.). The sequences corresponding to overlapping ATP8 and ATP6 genes are marked in cyan as in Figure 2. Peptide sequences removed in the mature form of yeast subunit a are marked in yellow. At the top and bottom, the arrows mark the locations of the human mutations (Table 2) and the mutations modeled in S.c., respectively. The arrows are colored according to Figure 4. At the bottom, the secondary structural elements are drawn according to PSIPRED prediction (2D) and a cryo-EM structure (3D) (Hahn et al., 2016).

Figure 4

Positions of human neurodegenerative disease-causing mutations in the structure of the yeast mitochondrial ATP synthase subunits a and 8 (human A6L). The views are from the matrix (A,B) and from the IMS (C,D) with detailed views in the IMS entry channel (B) and in the matrix exit channel (D). On (E,F), showing views along the membrane plane from outside the F_o stator and from the c-ring, respectively, the membrane borders are indicated as black lines. Subunits a, 8, and c are shown in blue, green, and yellow, respectively. The model is based on structural data from the Y. lipolytica and S. cerevisiae structures (Hahn et al., ; Guo et al., 2017). The positions of mutations, which have been found in human neurodegenerative diseases, are marked in white, red, blue, pink, orange and black for hydrophobic, negatively and positively charged, uncharged polar, proline and special residues, respectively. The mutations are labeled according to their positions in human subunit a listed in Table 2. The arrows indicate the path of protons in ATP synthesis direction. The conserved arginine (h.s. aR159, S.c. aR186) on helix aH5 is indicated by stick model; its orientation is randomly chosen. The figure was drawn with UCSF ChimeraX (Goddard et al., 2017).