Fig. 8: Schematic model for in situ HNO generation.
NO production of M1 macrophages together with the substantial number of lipoate groups in the PDH complex are conditions ripe for HNO generation and signaling. The interaction of NO with reduced lipoate-bound to PDH-E2 is likely to generate HNO together with oxidized lipoate as a resulting product. HNO resulting from exposure of NO to PDHE2-, will promptly target DLD due to proximity, together with other cellular proteins. Reaction with DLD thiols will form a sulfinamide modification. Modified Cys484 impairs dimerization and DLD activity compromising the entire PDH complex function. Since other mitochondrial dehydrogenases share DLD, this mechanism leads to repercussions on other major intracellular metabolic pathways. PDH pyruvate dehydrogenase, DLD dihydrolipoamide dehydrogenase, BCAA branched chain amino acid.
