Complex I: inhibitors, inhibition and neurodegeneration.

Complex I is the first protein component of the mitochondrial respiratory chain and as such plays a crucial role in ATP production and mitochondrial function in general. Mitochondrial dysfunction has been identified in a number of neurodegenerative diseases. In some of these the mitochondrial abnormality is primary and in others secondary. Mitochondrial toxins are capable of producing relatively selective neuronal cell death and have been used to produce models of human neurodegenerative diseases e.g. 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) for Parkinson's disease, and 3-nitropropionic acid for Huntington's disease. Annonacin, an ingredient of local soursop, is a Complex I inhibitor and has been incriminated as the cause of a parkinsonian tauopathy disorder in Guadeloupe. A systematic analysis has identified several environmentally available potent lipophilic Complex I inhibitors that can induce neuronal cell death in striatal cultures and somatodendritic redistribution of tau protein. It is possible that these compounds may contribute to the pathogenesis of neurodegenerative disorders, although further work must be done to confirm their potential participation in pathogenesis.