Proton leak during ATP synthesis

I was told there is a proton leak during ATP production. When going through the mechanisms we went over in class, I was unable to find when this occurs.


During what part of ATP production is there a proton leak and what are the ramifications of this?




This occurs during Oxidative phosphorylation and the "proton leak" process is also called **Uncoupling of Oxidative Phosphorylation**


**The mitochondrial electron-transport chain**


Electron transport, causes Complexes I, III, and IV to transport protons across the inner mitochondrial membrane from the matrix, a region of low [$\ce{H+}$] and negative electrical potential, to the intermembrane space (which is in contact with the cytosol), a region of high [$\ce{H+}$] and positive electrical potential.


[![enter image description here](https://i.stack.imgur.com/ayPjr.jpg)](https://i.stack.imgur.com/ayPjr.jpg)


Three of the four electron-transport complexes, Complexes I, III, and IV, are involved in proton translocation.
Two mechanisms have been put across that would couple the free energy of electron transport with the active transport of protons: the redox loop mechanism and the proton pump mechanism.


**Uncoupling of Oxidative Phosphorylation**


Electron transport (the oxidation of NADH and FADH2 by $\ce{O2}$) and oxidative phosphorylation (the synthesis of ATP) are normally tightly coupled due to the impermeability of the inner mitochondrial membrane to the passage of protons. Thus the only way for $\ce{H+}$ to re-enter the matrix is through the $\ce{F0}$ portion of the proton-translocating ATP synthase.



> 
> In the resting state, when oxidative phosphorylation is minimal, the
> proton-motive force across the inner mitochondrial membrane builds up
> to the extent that the free energy to pump additional protons is
> greater than the electron-transport chain can muster, thereby
> inhibiting further electron transport.
> 
> 
> However, many compounds,including 2,4-dinitrophenol (DNP) and
> carbonylcyanide-ptrifluoromethoxyphenylhydrazone (FCCP), have been
> found to “uncouple” these processes. In a pH gradient, they bind
> protons on the acidic side of the membrane, diffuse through, and
> release them on the alkaline side, thereby dissipating the gradient.
> 
> 
> 


The **chemiosmotic hypothesis** has provided a rationale for understanding the mechanism by which these uncouplers act.


*Uncouplers act by dissipating the proton gradient across the inner mitochondrial membrane created by the electron-transport system.*



> 
> As uncouplers, they function by carrying protons across the inner
> membrane. Their tendency is to acquire protons on the cytosolic
> surface of the membrane (where the proton concentration is high) and
> carry them to the matrix side, thereby destroying the proton gradient
> that couples electron transport and the ATP synthase.
> 
> 
> In mitochondria treated with uncouplers, electron transport continues
> and protons are driven out through the inner membrane. However, **they
> leak back in so rapidly via the uncouplers** that ATP synthesis does not
> occur. Instead, the energy released in electron transport is
> dissipated as heat.
> 
> 
> 


The presence in the inner mitochondrial membrane of an agent that renders it permeable to $\ce{H+}$ uncouples oxidative phosphorylation from electron transport by providing a route for the dissipation of the proton-motive force that does not require ATP synthesis. Uncoupling therefore **allows electron transport to proceed unchecked even when ATP synthesis is inhibited**.


[![enter image description here](https://i.stack.imgur.com/W8Jyu.png)](https://i.stack.imgur.com/W8Jyu.png)


*Uncoupling of oxidative phosphorylation: The proton-transporting ionophores DNP and FCCP uncouple oxidative phosphorylation from electron transport by discharging the electrochemical proton gradient generated by electron transport*


References


* Voet and Voet 4th ed. Biochemistry: Oxidative Phosphorylation
* R.H Garret & C.M Grisham Biochemistry 4th ed : Electron Transport and Oxidative phosphorylation


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