Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Abstract

We used electron cryotomography of mitochondrial membranes from wild-type and mutant Saccharomyces cerevisiae to investigate the structure and organization of ATP synthase dimers in situ. Subtomogram averaging of the dimers to 3.7 nm resolution revealed a V-shaped structure of twofold symmetry, with an angle of 86°between monomers. The central and peripheral stalks are well resolved. The monomers interact within the membrane at the base of the peripheral stalks. In wild-type mitochondria ATP synthase dimers are found in rows along the highly curved cristae ridges, and appear to be crucial for membrane morphology. Strains deficient in the dimer-specific subunits e and g or the first transmembrane helix of subunit 4 lack both dimers and lamellar cristae. Instead, cristae are either absent or balloon-shaped, with ATP synthase monomers distributed randomly in the membrane. Computer simulations indicate that isolated dimers induce a plastic deformation in the lipid bilayer, which is partially relieved by their side-by-side association. We propose that the assembly of ATP synthase dimer rows is driven by the reduction in the membrane elastic energy, rather than by direct protein contacts, and that the dimer rows enable the formation of highly curved ridges in mitochondrial cristae.membrane-protein oligomerization | membrane deformation | molecular dynamics simulations | bioenergetics | ATP synthesis T he F 1 F o ATP synthase is a highly conserved molecular machine that catalyses the production of ATP from ADP and P i in energy-converting membranes of eukaryotes and bacteria.

Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria

“…We have shown previously that the formation of inner-membrane cristae depends on the presence of ATP synthase dimers (6). Computer simulations indicate that the dimers induce membrane curvature, and not that, conversely, membrane curvature induces dimer formation (6).…”

“…Computer simulations indicate that the dimers induce membrane curvature, and not that, conversely, membrane curvature induces dimer formation (6). Yeast mutants in which the dimerspecific ATP synthase subunits e or g were knocked out lacked ATP synthase dimers, dimer rows, and lamellar cristae.…”

“…Each particle was connected to the membrane by a 4-nm stalk. Subtomogram averaging of the same particle pairs in yeast (6) and other organisms (1) has shown that they are dimers of the mitochondrial ATP synthase. Dimer rows were always present along the highly curved cristae tips in the partly lamellar morphology (Fig.…”

“…The inner mitochondrial membrane is highly folded into cristae (1)(2)(3), which contain the bulk of the respiratory chain complexes and the mitochondrial F 1 F o ATP synthase (4,5). At the cristae ridges, the ATP synthase self-assembles into long rows of dimers, which maintain a high local membrane curvature and normal cristae architecture (1,6,7). Respiratory chain complexes at either side of the dimer rows (1) pump protons from the mitochondrial matrix into the cristae space.…”

The mitochondrial respiratory chain of the secondary green alga Euglena gracilis shares many additional subunits with parasitic Trypanosomatidae

“…The dimeric nature of ATP synthase is now largely acknowledged in many organisms, and in mammals and yeasts, the dimer has a molecular mass of ~1.2 MDa and is thought also to be responsible for shaping mitochondrial cristae (Davies et al, 2012;Velours and Arselin, 2000;Walker et al, 1991). Beyond mammals, fungi and flowering plants, the first organism where an unusual structure and subunit composition of the mitochondrial ATP synthase was found was the green alga C. reinhardtii and its colourless relative Polytomella sp.…”