Ethylmalonic and Methylsuccinic Acids Disrupt Bioenergetics and Induce Mitochondrial Permeability Transition Through Thiol Redox Modulation in Rat Striatum: Potential Mechanisms Involved in Ethylmalonic Encephalopathy.

Ethylmalonic (EMA) and methylsuccinic (MSA) acids concentrations are elevated in tissues and body fluids of patients with ethylmalonic encephalopathy (EE), a mitochondrial disorder associated with basal ganglia abnormalities. To clarify the pathophysiology of this disorder, we evaluated the effects of EMA and MSA on bioenergetics, redox homeostasis and mitochondrial permeability transition (MPT) in rat striatum. We verified that EMA and MSA reduced state 3 and uncoupled respiration and inhibited the activities of α-ketoglutarate dehydrogenase and complex IV of the electron transport chain. Both organic acids also decreased mitochondrial membrane potential and Ca2+ retention capacity, which were normalized by cyclosporine A and ADP, indicating induction of MPT pore opening. These effects were further mitigated by N-ethylmaleimide and dithiothreitol, suggesting that thiol groups of the MPT pore were oxidized by EMA and MSA. Moreover, EMA and MSA mildly decreased reduced glutathione concentrations, reinforcing that thiol group are oxidized by these organic acids. Therefore, it is presumed that EMA- and MSA-induced bioenergetic impairment associated with MPT pore opening is involved in the pathophysiology of basal ganglia injury observed in EE.