Fragile mitochondrial DNA: the missing link in the apoptotic neuronal cell death in Parkinson's disease

The oxidative stress theory, the mitochondrial (mt) hypothesis, and the apoptosis hypothesis are proposed as the cause of neuronal cell death in Parkinson's disease (PD). However, the direct link between them has remained unknown. Recently, the mt control of nuclear apoptosis is documented that collapse of mt transmembrane potential due to energy crisis leads to release of apoptotic protease activating-factors into cytosol and subsequently nuclear DNA fragmentation. However, an endogenous factor responsible for the energy crisis under physiological conditions is missing. Here we report the missing factor as that mtDNA in the striatum of a parkinsonian patient fragments into 134 types of deleted pieces, being detected by the total detection system for mtDNA deletion. The system has documented that the mtDNA is extremely susceptible to hydroxyl radical damage, hence to oxidative stress, enough to cause the cellular energy crisis. The extensive fragility of mtDNA in brain stem could link the oxidative stress up with the apoptotic neuronal cell-death of PD.