Reversible uncoupling of oxidative phosphorylation at low oxygen tension.

Abstract

The stoichiometry of oxidative phosphorylation at low oxygen tension (< 3 torr; 02 < 5 aiM) has been measured in rat liver mitochondria. In a steady-state model in which respiration rate was experimentally controlled by either oxygen or substrate (succinate) limitation, flux-dependent variation in the phosphorylation efficiency (P/O ratio) of stimulated mitochondrial respiration was evaluated. P/O ratio remained constant over a wide range of respiration rates in mitochondria limited only by substrate availability. In contrast, oxygen-limited mitochondria demonstrated a continuous decline in P/O ratio as respiration was increasingly restricted. Significant differences in the two test conditions were demonstrated throughout the range of analysis. The effect of oxygen limitation on phosphorylation efficiency was shown to be completely reversed by restoring zero-order kinetics associated with high oxygen tension. These findings are discussed in regard to a proposed uncoupling of mitochondrial coupling site II at low oxygen tension arising as a consequence of energy-dissipating electron flux through the ubiquinone-cytochrome b-cl region of the respiratory chain (complex III).Living cells utilize and conserve energy in various forms. In this regard, the cell shares with other mixed-energy-domain systems the ability to convert energy internally from one physical form to another. For aerobic organisms, the existence of one such biological energy transduction has been extensively documented: the coupling of electron transport in the mitochondrial respiratory chain (cellular respiration) to the synthesis of ATP. Indeed, so effectively does oxidative phosphorylation support the many energy-requiring reactions of aerobic cells that there is a tendency to assume that mitochondrial ATP synthesis proceeds with maximum stoichiometric efficiency under nearly all physiologic conditions. However, it is well established that mitochondrial respiration is not obligatorily linked to the formation of high-energy phosphate bonds (1-4). The phenomenon of uncoupling has been demonstrated routinely in the laboratory by using chemical agents that direct the energy released by electron transport into mitochondrial energetic activities other than phosphorylation. The possibility of intrinsic mitochondrial uncoupling has been considered by several investigators and is predicated on the hypothetical existence of energy-dissipating pathways of electron flux through the respiratory chain. In this connection, Trumpower (5) commented on a potential uncoupling of Mitchell's proposed "Q-cycle" (6) related to the disposition of the unpaired electron of ubisemiquinone interacting with the Rieske iron-sulfur protein at coupling site II. An explicit separation of energy-transducing and energy-dissipating electron transport pathways in submitochondrial particles is described in the dual respiratory chain model of Norling et al. (7). Chance (8) proposed energy-dissipating electron flux between quasi-equipotential carrier groups to explain the init...

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