Dysfunction of mitochondrial Lon protease and identification of oxidized protein in mouse brain following exposure to MPTP: Implications for Parkinson disease.

Compelling evidence suggests that mitochondrial dysfunction leading to reactive oxygen species (ROS) production and protein oxidation could represent a critical event in the pathogenesis of Parkinson's disease (PD). Pioneering studies have shown that the mitochondrial matrix contains the Lon protease, which degrades oxidized, dysfunctional, and misfolded protein. Using the PD animal model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication in mice, we showed that Lon protease expression increased in the ventral mesencephalon of intoxicated animals, concomitantly with the appearance of oxidized proteins and dopaminergic cell loss. In addition, we report that Lon is inactivated by ROS. Moreover, proteomic experiments provide evidence of carbonylation in α-ketoglutarate dehydrogenase (KGDH), aconitase or subunits of respiratory chain complexes. Lon protease inactivation upon MPTP treatment in mice raises the possibility that Lon protease dysfunction is an early event in the pathogenesis of PD.