The mitochondrial F₁F_O-ATPase exploits the dithiol redox state to modulate the permeability transition pore

The dithiol reagents phenylarsine oxide (PAO) and dibromobimane (DBrB) have opposite effects on the F₁F_O-ATPase activity. PAO 20% increases ATP hydrolysis at 50 μM when the enzyme activity is activated by the natural cofactor Mg²⁺ and at 150 μM when it is activated by Ca²⁺. The PAO-driven F₁F_O-ATPase activation is reverted to the basal activity by 50 μM dithiothreitol (DTE). Conversely, 300 μM DBrB decreases the F₁F_O-ATPase activity by 25% when activated by Mg²⁺ and by 50% when activated by Ca²⁺. In both cases, the F₁F_O-ATPase inhibition by DBrB is insensitive to DTE. The mitochondrial permeability transition pore (mPTP) formation, related to the Ca²⁺-dependent F₁F_O-ATPase activity, is stimulated by PAO and desensitized by DBrB. Since PAO and DBrB apparently form adducts with different cysteine couples, the results highlight the crucial role of cross-linking of vicinal dithiols on the F₁F_O-ATPase, with (ir)reversible redox states, in the mPTP modulation.