From the Guidelines
Dinitrophenol acts as an uncoupler of oxidative phosphorylation by allowing for proton exchange across the inner mitochondrial membrane. This mechanism is supported by the study published in Cell Death and Differentiation in 2018 1, which lists DNP as a protonophore that increases proton leak and uncouples mitochondria. The study explains that protonophores like DNP create a H+ short-circuit across the mitochondrial inner membrane, decreasing the proton-motive force and allowing respiration to increase.
The normal process of ATP production in mitochondria involves the electron transport chain pumping protons across the inner mitochondrial membrane, creating a proton gradient that drives ATP synthesis when protons flow back through ATP synthase. However, DNP, being lipophilic and weakly acidic, can carry protons across the membrane, effectively creating a "short circuit" that allows protons to bypass ATP synthase. As a result, the energy from the proton gradient is dissipated as heat rather than being used for ATP synthesis.
Key points about the mechanism of DNP include:
- It increases proton leak across the inner mitochondrial membrane
- It uncouples mitochondria, disrupting the normal process of ATP production
- It creates a H+ short-circuit across the mitochondrial inner membrane, decreasing the proton-motive force
- It allows respiration to increase, with substrate oxidation becoming the dominant controller of O2 consumption.
The study 1 provides guidelines for the use of DNP and other protonophores in experimental settings, including optimal concentrations and potential off-target effects. However, the key takeaway is that DNP acts by allowing for proton exchange across the inner mitochondrial membrane, which has significant implications for its effects on cellular metabolism and energy production.
From the Research
Mechanism of Dinitrophenol
- Dinitrophenol acts as an uncoupler of oxidative phosphorylation by allowing for proton exchange across the inner mitochondrial membrane 2, 3, 4.
- This mechanism is supported by studies that show DNP increases mitochondrial proton leak, leading to a decrease in the efficiency of oxidative phosphorylation 3, 4.
- The uncoupling effect of DNP is thought to be due to its ability to dissipate the proton gradient across the inner mitochondrial membrane, allowing protons to leak back across the membrane without generating ATP 4, 5.
- This leads to an increase in oxygen consumption and a decrease in ATP production, resulting in weight loss 2, 6, 4.
Comparison of Mechanisms
- Activating the H+-ATPase is not a mechanism by which DNP acts as an uncoupler of oxidative phosphorylation 3, 4.
- Activating CoQ is also not a mechanism by which DNP acts as an uncoupler of oxidative phosphorylation 3, 4.
- Blocking proton transport across the inner mitochondrial membrane is the opposite of what DNP does, as it allows for proton exchange across the membrane 3, 4.
- Enhancing oxygen transport across the inner mitochondrial membrane is not a direct mechanism by which DNP acts as an uncoupler of oxidative phosphorylation, although it does lead to an increase in oxygen consumption 4, 5.