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Comment
. 2022 Apr 19;3(3):zqac018.
doi: 10.1093/function/zqac018. eCollection 2022.

Setting the Record Straight: A New Twist on the Chemiosmotic Mechanism of Oxidative Phosphorylation

Magdalena Juhaszova  1 , Evgeny Kobrinsky  1 , Dmitry B Zorov  1 , Miguel A Aon  1 , Sonia Cortassa  1 , Steven J Sollott  1
Affiliations
Comment

Setting the Record Straight: A New Twist on the Chemiosmotic Mechanism of Oxidative Phosphorylation

Magdalena Juhaszova et al. Function (Oxf). .
No abstract available

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Figures

Figure 1.
Figure 1.
Comparison and functional implications of alternate models of ion-directed energy coupling in ATP synthase. (A) Chemiosmotic theory extended by the capacity of ATP synthase to utilize K+, H+ (and Na+) electrogenic uniport to drive ATP synthesis. The respiratory chain pumps protons out of the matrix setting up an inward-directed H+ gradient with energy components stored as ΔΨm and ΔpH. These energies (mainly ΔΨm) are used by driving H+, K+ (and Na+) back into the matrix via an electrogenic translocation path enabling them to perform work (by exerting torque on the Fo  c-ring) and turning the Fo rotary motor in ATP synthase, and in a mechanochemical energy transduction with the F1 catalytic complex of ATP synthase, produces ATP from ADP + Pi in the mitochondrial matrix. K+ and H+ each occupy (but physically separately) the same ion-binding locations on the c-ring of the Fo motor in ATP synthase. In the standard “H+-only”-running model of chemiosmotic theory, all eight positions on the c-ring (in the mammalian Fo) would be H+ (shown as green balls, as in Panel B). In our model shown here, of the eight c-ring positions, on average approximately six will be occupied by K+ (red balls) and two will be occupied by H+ (in a net ratio of ∼3:1) in a random ordering, to produce three ATP for a full c-ring turn with the translocation of those eight ions (N.B., for clarity, 5 K+ and 3 H+ are shown on the c-ring in the illustration; since only ∼1 Na+ is translocated for every 24 cations driving ATP synthase, it is not shown; the direction of ion movement shown here in Fo is for convenient illustration purposes only—the actual direction of rotation is clockwise for ATP synthesis, with the ion entrance and exit “hemichannels” arranged respectively). The resulting matrix-accumulated K+ is then extruded via a separate (kinetically phase-lagged) K+/H+ exchanger. The electrogenic uniport of K+ by ATP synthase is adaptive and workload dependent, producing relevant osmotic-driven signals that control matrix volume changes that in turn result in activation of the respiratory chain (volume-activation of respiration mechanism), serving as feedback for matching energy supply with demand. See text and accompanying references for details. (B) Nath's electroneutral “two-ion” theory of energy coupling. According to Nath's electroneutral “two-ion” theory the primary redox energy-harnessing step at the respiratory chain is the net electroneutral pumping of H+ out of the matrix in exchange for K+, which secondarily generates ΔpK on the matrix side (together with ΔpH on the intermembrane space side). Then, harnessing the newly formed ΔpK, K+ is translocated first from the matrix down its concentration gradient by a postulated K/H antiport mechanism residing within the ATP synthase. The resulting K+ movement-related local charge separation generates a temporary, localized ΔΨm (within the ATP synthase complex itself) that electrostatically attracts H+, enabling translocation of H+ and binding to the c-ring (producing torque, etc.), and ultimately (together with ΔpH) driving H+ back into the matrix. Except for H+ using a putative, coupled ion-antiport/translocation activity (structurally uncorroborated and unverified by any physical measurement technique) hypothetically occurring at the a-c-subunits’ interface of Fo to access the c-ring (Panel B), rather than using the accepted, structurally identified a-subunit aqueous access half-channels (as depicted in Panel A; e.g., for bovine structure, see , and references therein for concordant structural evidence across taxonomic domains), the subsequent processes apparently involve the standard “H+-only”-running model to drive ATP synthase, with all positions on the Fo  c-ring bound exclusively by H+ (shown as green balls). While this latter K/H-exchanged energy (together with that of ΔpH) transferred back to H+ is finally used to drive ATP synthesis, another important distinction in this model (vs that depicted in Panel A) is that K+  neither binds to, nor has its energy directly harnessed to turn the c-ring. In fact, the vector direction of this latter ATP synthase-antiported K+ movement (resulting from the putative K/H exchange activity) is exactly the opposite of that depicted in the model shown in Panel A. This process would produce apparently paradoxically maladaptive reciprocal changes in matrix K+ and workload, by retaining higher matrix K+, volumes and respiratory activities at low workloads, and in the opposite case, causing a lower matrix K+, volumes and respiratory activities at high workloads, which would serve the opposite purposes required for appropriate energy supply-demand matching. Because all these ion exchange processes are net electroneutral, the bulk phase ΔΨm is functionally irrelevant in this model.
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References

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