Figure 2.

Mitochondrial uncoupling reprograms metabolism and epigenetic landscape (A) Mitochondrial uncouplers dissipate the proton gradients which are essential to ATP synthesis, resulting in reduction of ATP/ADP ratio. When proton gradient reduce, the electron transfer chain, particularly complex I, are activated, leading to increased intracellular redox NAD⁺/NADH ratio. Given the NAD⁺/NADH ratio is the major driving force for TCA cycle, the oxidative TCA cycle and glutaminolysis are accelerated. Because the chemical equilibrium of many metabolites pair such as α-KG/2-HG and pyruvate and lactate (not show in the figure) are dictating by NAD⁺/NADH ratio. Thus, increased NAD⁺/NADH mediated by mitochondrial uncoupler shift the equilibrium from 2-HG to α-KG, resulting in increased α-KG/2-HG ratio. In the other hand, opposite to the oxidative TCA cycle, the reductive TCA cycle particular reductive carboxylation is inhibited by mitochondrial uncoupler. (B) The increased α-KG/2-HG ratio activates the α-KG-dependent dioxygenases such as TET and PHD, leading to DNA demethylation and HIFs protein degradation. These epigenetic rewiring activate the expression of differentiation makers and repress the stemness genes, consequently, cell differentiation. Created with >BioRender.com.