Theory of ATP and cAMP mediated regulation of Complex I and potential sites of NRTI inhibition. An increase in mitochondrial ATP can lead to two states of complex I, depending on the availability of cAMP. In the absence of cAMP, ATP causes a decrease in activity and an increase in superoxide generation by an unknown process, potentially by allosteric inhibition, alteration in divalent cation concentration, or increasing ΔpH across the inner membrane. In the presence of cAMP, AKAP localized PKA is activated/released from its regulatory subunits and phosphorylates complex I at the ESSS and MWFE phosphorylation sites leading to an increase in activity and a decrease in superoxide production. The hypothesized points of NRTI inhibition of this process occur at the four indicated points: 1) cAMP binding to the tetrameric PKA complex, thus preventing PKA activation, or 2) PKA’s phosphorylation of complex I (by interfering with the ATP/ADP binding site of PKA, 3) some combination of ATP, PKA, and complex I binding, or 4) inhibition of an unknown cAMP-dependent kinase which phosphorylates complex I.
ADP, adenosine 5′-diphosphate, AKAP, A kinase anchor protein; ATP, adenosine 5′-triphosphate, cAMP, adenosine 3′,5′-cyclic monophosphate; NRTI, nucleoside reverse transcriptase inhibitor;PKA, protein kinase A