ORNT2 Inhibitors

Chemical inhibitors of ORNT2 target the protein's function in various ways, primarily by disrupting the mitochondrial membrane potential and the exchange of substrates that ORNT2 mediates. Carboxyatractyloside, atractyloside, and atracyloside potassium salt inhibit ORNT2 by directly blocking its substrate binding sites. This prevents ORNT2 from facilitating the transport of substrates across the mitochondrial membrane, which is its primary function. Bongkrekic acid, while also targeting the adenine nucleotide translocase, does so by binding to a different site than carboxyatractyloside, preventing the necessary conformational change for ADP/ATP exchange and thus inhibiting ORNT2's activity. Glibenclamide functions differently; it blocks mitochondrial ATP-sensitive potassium channels, indirectly affecting the mitochondrial membrane potential, which is a critical factor for the function of ORNT2.

Further impacting the mitochondrial membrane dynamics and the function of ORNT2 are chemicals like phloretin, which disrupts the lipid bilayer, and Cyclosporin A, which inhibits the mitochondrial permeability transition pore complex. Both actions can lead to disturbances in the mitochondrial membrane potential, impairing ORNT2 activity. Disrupting the electron transport chain is another strategy for inhibiting ORNT2. Resveratrol achieves this by inhibiting complexes I and III, subsequently altering mitochondrial membrane dynamics. In a similar vein, Rotenone inhibits mitochondrial complex I, reducing the membrane potential required for ORNT2's transport activity. 2,4-Dinitrophenol and FCCP (Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) are both protonophores that uncouple oxidative phosphorylation, collapsing the mitochondrial membrane potential and, consequently, inhibiting ORNT2. Lastly, oligomycin targets ATP synthase, causing an increase in mitochondrial membrane potential, which can also lead to the inhibition of ORNT2 by altering its normal function.