SLC25A44 Inhibitors

Chemical inhibitors of SLC25A44 function by interfering with the cellular and biochemical processes that are integral to the protein's activity in mitochondrial ATP/ADP exchange. Bongkrekic acid, atractyloside, and carboxyatractyloside all target the adenine nucleotide translocase (ANT), which is essential for the transport of ADP into the mitochondria and ATP out of the mitochondria. By binding to and inhibiting ANT, these chemicals deprive SLC25A44 of its substrates, thereby inhibiting its function. Glibenclamide acts on ATP-sensitive potassium channels; by blocking these channels, the mitochondrial membrane potential is altered. This change in membrane potential can disrupt the proton gradient necessary for SLC25A44 to facilitate the exchange of ATP and ADP across the mitochondrial membrane.

Further impacting the mitochondrial membrane potential and proton gradient, chemicals like decylubiquinone, TTFA, malonate, antimycin A, oligomycin, FCCP, and rotenone inhibit various components of the mitochondrial electron transport chain. Decylubiquinone is a coenzyme Q analog that impedes electron transport, thereby diminishing the proton gradient across the mitochondrial membrane, a gradient that SLC25A44 relies on for its transport mechanism. TTFA and malonate inhibit mitochondrial complex II, antimycin A inhibits complex III, and oligomycin acts on ATP synthase (complex V). All of these inhibit the generation of a proton gradient required for SLC25A44's function in ATP/ADP exchange. FCCP, a mitochondrial uncoupler, actively dissipates the proton gradient, leading to a direct inhibition of SLC25A44 because the protein's activity is dependent on a strong proton motive force. Lastly, rotenone's inhibition of complex I of the electron transport chain also leads to a reduced proton gradient, similar to the effect of the other mitochondrial inhibitors, culminating in the inhibition of SLC25A44 activity.