ATP synthase: From sequence to ring size to the P/O ratio

Abstract

There are tales of P/O battles at conferences in the 1950s. P/O is the number of ATP molecules synthesized by oxidative phosphorylation for each pair of electrons (hence, not P/O2) passing from a particular substrate, typically NADH or succinate, via a respiratory chain, to O2. Knowledge of the P/O ratio is fundamental for understanding the ATP yield from cell fuels and is a core metabolic parameter. The battles of old persisted because the P/O ratio is difficult to measure. Determination of O2 consumed became easier as manometers were replaced by electrodes, but calibration is difficult because the dissolved O2 concentration depends on temperature, ionic strength, history of the solution, and atmospheric pressure. Determining ATP made by suspensions of (usually animal) mitochondria is also error prone. Furthermore, mitochondria might be damaged, either homogeneously or heterogeneously, and thus provide underestimates of the P/O ratio because O2 consumption can proceed without full coupling to ATP synthesis, e.g., owing to leakage of protons across membranes. The combatants in the P/O battles of the 1950s could never have imagined that P/O ratios might be assessed via structural biology, as illustrated by a study (1) in PNAS. Many biochemists also have not contemplated that a highly conserved enzyme has a variable relative subunit stoichiometry. The paper (1) unexpectedly shows variation in the stoichiometry of one critical subunit, c, among ATP synthases of mitochondria from different sources.