Respiratory complex II in mitochondrial dysfunction-mediated cytotoxicity: Insight from cadmium

In the present work we studied action of several inhibitors of respiratory complex II (CII) of mitochondrial electron transport chain, namely malonate and thenoyltrifluoroacetone (TTFA) on Cd²⁺-induced toxicity and cell mortality, using two rat cell lines, pheochromocytoma PC12 and ascites hepatoma AS-30D and isolated rat liver mitochondria (RLM). It was shown that malonate, an endogenous competitive inhibitor of dicarboxylate-binding site of CII, restored in part RLM respiratory function disturbed by Cd²⁺. In particular, malonate increased both phosphorylating and maximally uncoupled respiration rates in KCl medium in the presence of CI substrates as well as palliated changes in basal and resting state respiration rates produced by the heavy metal on the mitochondria energized by CI or CII substrates. Notably, malonate enhanced Cd²⁺-induced swelling of the mitochondria energized by CI substrates in KCl and, in a much lesser extent and at higher [Cd²⁺], in sucrose media but did not influence on the Cd²⁺ effects in NaCl medium. Besides, malonate did not affect swelling in sucrose media of RLM energized by CIV substrates under using of Cd²⁺ or Ca²⁺ whereas it strongly increased the mitochondrial swelling produced by selenite. In addition, malonate produced some protection against Cd²⁺-promoted necrotic death of AS-30D and PC12 cells and reduced intracellular reactive oxygen species (ROS) formation evoked by Cd²⁺ in PC12 cells. Importantly, TTFA, an irreversible competitive inhibitor of Q-binding site of CII, per se induced apoptosis of AS-30D cells which was inhibited by co-treatment with Cd²⁺ as well as decreased the Cd²⁺-enhanced intracellular ROS formation. In turn, decylubiquinone (dUb) at low μM concentrations did not protect AS-30D cells against the Cd²⁺-induced necrosis and enhanced the Cd²⁺-induced apoptosis of the cells. High μM concentrations of dUb were highly toxic for the cells. As consequence, the findings give new evidence indicative of critical involvement of CII in mechanism(s) of Cd²⁺-produced cytotoxicity and support the notion on CII as a perspective pharmacological target in mitochondria dysfunction-mediated conditions and diseases.