Mitochondrial complex I defects increase ubiquitin in substantia nigra

Parkinson׳s disease (PD) is the second most common neurodegenerative disorder in the developed world, and is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) of midbrain. Mitochondrial complex I dysfunction has been implicated in PD pathophysiology, yet the molecular mechanism by which complex I defects may cause DA neurodegeneration remain unclear. Using Ndufs4 mouse model of mitochondrial complex I deficiency, we observed a remarkable ubiquitin protein increase in SN of Ndufs4-/- (KO) mice. By contrast, neurofilaments were significantly decreased in SN of KO mice. Furthermore, mass spectrometry and co-immunoprecipitation (Co-IP) analysis indicated an increase in ubiquitinated neurofilaments in midbrain of KO mice, whereas 20S proteasome activities were decreased, which could potentially explain the buildup of ubiquitin protein. Collectively, these data suggest that mitochondrial complex I defects cause proteasome inhibition, a consequent increase in ubiquitinated neurofilaments and other proteins, and decrease the expression of neurofilaments that could be relevant to the mechanism of DA neuronal death in PD.