Mitochondrial dysfunction in neurodegeneration.

Abstract

Numerous toxins are known to interfere with mitochondrial respiratory chain functions. Use has been made of these in the development of pesticides and herbicides, and accidental use in man has led to the development of animal models for human disease. The propensity for mitochondrial toxins to induce neuronal cell death may well reflect not only their metabolic pathways but also the sensitivity of neurons to inhibition of oxidative phosphorylation. Thus, the accidental exposure of humans to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and to 3-nitropropionic acid had led to primate models of Parkinson's disease and Huntington's Disease, respectively. These models were made all the more remarkable when identical biochemical deficiencies were identified in relevant areas of human suffering from the respective idiopathic diseases. The place of complex I deficiency in Parkinson's disease remains undetermined, but there is recent evidence to suggest that, in some cases at least, it may play a primary role. The complex II/III deficiency in Huntington's disease is likely to be secondary and induced by other pathogenetic factors. The potential to intervene in the cascade of reactions involving mitochondrial dysfunction and cell death offers prospects for the development of new treatment strategies either for neuroprotection in prophylaxis or rescue.