Mitochondrial F-type ATP synthase: multiple enzyme functions revealed by the membrane-embedded F_O structure

Abstract

Of the two main sectors of the F-type ATP synthase, the membrane-intrinsic FO domain is the one which, during evolution, has undergone the highest structural variations and changes in subunit composition. The FO complexity in mitochondria is apparently related to additional enzyme functions that lack in bacterial and thylakoid complexes. Indeed, the F-type ATP synthase has the main bioenergetic role to synthesize ATP by exploiting the electrochemical gradient built by respiratory complexes. The FO membrane domain, essential in the enzyme machinery, also participates in the bioenergetic cost of synthesizing ATP and in the formation of the cristae, thus contributing to mitochondrial morphology. The recent enzyme involvement in a high-conductance channel, which forms in the inner mitochondrial membrane and promotes the mitochondrial permeability transition, highlights a new F-type ATP synthase role. Point mutations which cause amino acid substitutions in FO subunits produce mitochondrial dysfunctions and lead to severe pathologies. The FO variability in different species, pointed out by cryo-EM analysis, mirrors the multiple enzyme functions and opens a new scenario in mitochondrial biology.

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

“…This amazing rotary enzyme complex offers a good example of how molecular structure and function are tightly linked features [ 130 ], which cannot work without each other.…”

“…By self-assembling in dimers and tetramers, the F 1 F O -ATPase rules most bioenergetic and structural functions in eukaryotic mitochondria [ 159 ]. Accordingly, the occurrence of sms , which lack in bacteria and chloroplasts, in F O is linked to the sms involvement in supercomplex arrangement and in the mtIM ultrastructure [ 130 ]. Consistently, no F 1 F O -ATPase dimers were found in prokaryotes and chloroplasts, while some differences between yeast and mammalian F 1 F O -ATPases occur in the building of contact sites.…”

“…This amazing rotary enzyme complex offers a good example of how molecular structure and function are tightly linked features [130], which cannot work without each other. In mammalian mitochondria, this astonishing enzyme complex has recently revealed versatile roles, in addressing cells to life or death, in the maintenance of the mitochondrial morphology and raised great expectations as a drug target [129,130].…”

“…This amazing rotary enzyme complex offers a good example of how molecular structure and function are tightly linked features [130], which cannot work without each other. In mammalian mitochondria, this astonishing enzyme complex has recently revealed versatile roles, in addressing cells to life or death, in the maintenance of the mitochondrial morphology and raised great expectations as a drug target [129,130]. Accordingly, the modulation of the enzyme functions, often compromised by mitochondrial dysfunctions associated with severe diseases, may contribute to innovative therapeutic strategies at the molecular level.…”

Ca2+ as cofactor of the mitochondrial H+‐translocating F1FO‐ATP(hydrol)ase

“… 4 The H + translocation sector arises from a/c ‐ring interactions by forming two asymmetric half‐channels with unexpected horizontal membrane‐intrinsic α‐helices in the a subunit. These two half‐channels are mutually offset, while the H + binding sites are located on the C‐terminal α‐helix of each c subunit 5 . In the mammalian F 1 F O ‐ATPase the a and A6L membrane subunits are encoded by the mitochondrial DNA.…”