ACAD-9 Inhibitors

Chemical inhibitors of ACAD-9 can exert their inhibitory effects through various mechanisms impacting mitochondrial function and fatty acid oxidation. Etravirine disrupts mitochondrial function and thereby can inhibit ACAD-9 activity by impairing the electron transport chain, a crucial process for the fatty acid oxidation that ACAD-9 facilitates. Diphenyleneiodonium chloride, by inhibiting NADPH oxidase, decreases reactive oxygen species production, leading to reduced oxidative stress. This alteration in redox-sensitive signaling pathways can indirectly inhibit ACAD-9, as it is an enzyme sensitive to the cellular redox state. Malonate serves as a competitive inhibitor of succinate dehydrogenase, leading to an accumulation of NADH and subsequent inhibition of NAD+-dependent enzymes, including ACAD-9, by reducing the availability of NAD+ which is necessary for the dehydrogenation steps in fatty acid oxidation.

Tenovin-6, through the inhibition of SIRT1, can lead to the hyperacetylation of PGC-1α, resulting in decreased PGC-1α activity and consequently diminished mitochondrial fatty acid oxidation capacity where ACAD-9 is operational. The chelating action of 2-Thenoyltrifluoroacetone on essential metal ions like Mg2+ and Mn2+ can potentially inhibit enzymes that require these ions, including ACAD-9. Oligomycin's inhibition of ATP synthase reduces mitochondrial membrane potential, which can indirectly inhibit ACAD-9 by limiting the energy available for its fatty acid oxidation activity. Cerulenin inhibits fatty acid synthase, which leads to reduced levels of fatty acids, indirectly inhibiting ACAD-9 by decreasing substrate availability. Perhexiline and Sulfo-N-succinimidyl oleate inhibit the transport of fatty acids into mitochondria, thereby potentially reducing the substrate availability for ACAD-9. Further along the electron transport chain, Antimycin A and Rotenone inhibit complexes III and I, respectively, disrupting mitochondrial energy metabolism, which can indirectly inhibit ACAD-9 by reducing the energy production necessary for its fatty acid oxidation function. Lastly, Metformin activates AMPK, which can inhibit fatty acid synthesis, reducing substrate availability for ACAD-9, thus indirectly inhibiting its activity in mitochondrial fatty acid oxidation.