The “B Space” of mitochondrial phosphorylation

Abstract

It was recently shown that, in progressively depolarizing mitochondria, the F(0) -F(1) ATP synthase and the adenine nucleotide translocase (ANT) may change directionality independently from each other (Chinopoulos et al. [2010] FASEB J. 24:2405). When the membrane potentials at which these two molecular entities reverse directionality, termed reversal potential (Erev), are plotted as a function of matrix ATP/ADP ratio, an area of the plot is bracketed by the Erev_ATPase and the Erev_ANT, which we call "B space". Both reversal potentials are dynamic, in that they depend on the fluctuating values of the participating reactants; however, Erev_ATPase is almost always more negative than Erev_ANT. Here we review the conditions that define the boundaries of the "B space". Emphasis is placed on the role of matrix substrate-level phosphorylation, because during metabolic compromise this mechanism could maintain mitochondrial membrane potential and prevent the influx of cytosolic ATP destined for hydrolysis by the reversed F(0) -F(1) ATP synthase.

Mitochondrial membrane potential

“…As noted above, the rotational direction of ATP synthase can lead to either the synthesis of ATP at the expense of ΔΨm (at clockwise rotation of ATP synthase complex) or to the hydrolysis of ATP, leading to the generation of ΔΨm (at counterclockwise rotation of ATP synthase complex) [43]. In addition, the membrane potential can be supported by the reverse operation of ANT importing cytosolic ATP into mitochondria in exchange for mitochondrial ADP [44,45]. We may conclude, the higher is the level of intracellular ATP, the more stable are the ΔΨm values, making ATP a compound buffering ΔΨm.…”

Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells

“…As stated above, the threshold of mPT opening depends on the extent of ΔΨm; de-energization by cyanide in the abscence of glucose would lead to reversal of the mitochondrial ATP synthase in an attempt to maintain membrane potential, at the expense of hydrolysing ATP originating from either cytosol (glycolysis) or mitochondrial substrate-level phosphorylation4647484950. Thus, during the de-energization protocol and in the presence of calcimycin, a complete collapse of ΔΨm in our cell lines is not warranted and the presence of a residual potential value is more than likely.…”

Differential Mitochondrial Function in Remodeled Right and Nonremodeled Left Ventricles in Pulmonary Hypertension

“…We speculate that this unexpected finding could result from changes in the inner membrane composition and surface area [32]. Additionally, it is possible that compensatory proton pumping that does not increase oxygen consumption such as the socalled "B-Space" condition in which F 0 -F 1 ATP synthase operates in reverse direction to translocate protons back out of the matrix could account for this paradox [33]. Mitochondrial OXPHOS protein expression was not significantly different for the RM-RV and NRM-LV groups, suggesting that M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 13 differences in mitochondrial function maybe related to upstream factors such as mitochondrial uptake of protein precursors and ATP/ADP and metabolism of substrates like pyruvate and fatty acids.…”

“…changes in unsaturated fatty acid and n-3 polyunsaturated fatty acid content) and differences in inner mitochondrial membrane surface area [32] could blunt the high-voltage dependency of proton leak [32,33]. Further, it is possible that state 4 rates for succinate may be elevated in the RM-RV due to complex II ROS production [34][35][36].…”