Figure 1.

NEN-mediated mitochondrial uncoupling & Study design. (a) NADH and FADH₂ reducing equivalents from upstream mitochondrial metabolism enter the mitochondrial respiratory chain. As they travel along the respiratory chain, complexes I – IV pump protons from the mitochondrial matrix to the intermembrane space. ATP synthase/complex V uses this proton gradient to generate ATP. NEN allows protons to pass back into the mitochondrial matrix, bypassing ATP synthase-mediated ATP production. Thus, mitochondrial respiration is uncoupled from energy production. This “release” of the proton gradient allows more reducing equivalents from NADH and FADH₂ to enter the respiratory chain, increasing upstream fatty acid oxidation and TCA cycling (represented by red font). (b) Study design. 1. Metabolic phenotyping, 2. diabetic peripheral neuropathy, diabetic kidney disease, and diabetic retinopathy phenotyping, 3. dorsal root ganglion neuron mitochondrial coupling efficiency. NEN, niclosamide ethanolamine.