CH 21: The Proton-Motive Force

21.1 A Proton Gradient Powers ATP Synthesis

Proton-Motive Force (pmf):
Defined as the proton gradient created by the oxidation of NADH and FADH₂, it is essential for ATP synthesis. The pmf is more than just a chemical gradient; it serves as a driving force for ATP production by establishing both a chemical gradient (ΔpH) and a charge gradient (ΔΨ), expressed as:

ext{Proton-motive force} ext{ (Δp)} = ext{chemical gradient (ΔpH)} + ext{charge gradient (ΔΨ)}

21.1.1 Structure of ATP Synthase
Composition:

• F₀ Component:

  • Embedded in the inner mitochondrial membrane; it contains the proton channel and the c-ring (rotor).

• F₁ Component:

  • Protrudes into the mitochondrial matrix and includes the active sites for ATP synthesis. The cristae of the mitochondria enhance the surface area for ATP production, optimizing the efficiency of ATP synthase.

21.1.2 The Binding-Change Mechanism

The catalytic β subunits of ATP synthase alternate among three conformations, which are crucial for ATP synthesis:

• O (Open): Allows nucleotides and inorganic phosphate (Pi) to bind/release.

• L (Loose): Traps nucleotides.

• T (Tight): Synthesizes ATP from ADP and Pi.
  The rotation of the γ subunit facilitates these conformational changes, allowing for efficient ATP production as protons flow through the F₀ component.

21.1.3 Mechanism of Proton Flow and ATP Synthesis

Proton entry through F₀:
Protons enter via a half-channel exposed to the intermembrane space, bind to glutamate of the c ring, and exit into the mitochondrial matrix after rotation. This proton flow induces the rotation of the c ring, which in turn initiates movement in the γ subunit, altering the conformational state of the β subunits to promote ATP synthesis. The number of c subunits dictates the number of protons required to produce a single ATP molecule.

21.2 Shuttles Allow Movement Across Mitochondrial Membranes

Glycerol Phosphate Shuttle:
This shuttle is utilized in muscles to transport electrons from cytoplasmic NADH to the mitochondrial electron transport chain by converting NADH into FADH₂.

Malate-Aspartate Shuttle:
This system functions in heart and liver cells to convert cytoplasmic NADH into mitochondrial NADH, ensuring proper electron transport and energy production.

21.3 Regulation of Cellular Respiration

Regulation of cellular respiration is crucial for maintaining energy balance. One key concept in this regulation is acceptor control, which states that the presence of ADP is essential for the activity of ATP synthase. If ADP is not available, the flow of electrons ceases, halting ATP production.

ATP Yield from Glucose Oxidation:

• Complete oxidation yields 30 molecules of ATP (net).

• Breakdown of ATP yield:

  • Glycolysis: 2 ATP (net) / 4 ATP (gross)

  • Remaining 28 ATP from oxidative phosphorylation.

• Comparison to fermentation: only 2 ATP produced per glucose molecule, indicating a 15x efficiency increase in ATP production.

21.4 Biological Insight: Heat Generation
UCP-1 (Thermogenin) facilitates the uncoupling of electron transport from ATP synthesis, leading to heat production known as non-shivering thermogenesis, which is critical for thermoregulation.

21.5 Clinical Insight: Inhibition of Oxidative Phosphorylation
Inhibition of the electron transport chain stops oxidative phosphorylation, thereby hindering the formation of the proton-motive force. Specific inhibitors can obstruct ATP synthase by preventing proton flow, resulting in detrimental effects on the energy production capability of cells.