Reversal of Mitochondrial Damage Caused by Environmental Neurotoxins
Annual rept. 1 Sep 1999-1 Sep 2000
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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The basic premise is that the turnover of dopamine DA by monoamine oxidase MAO places an oxidative stress on the mitochondria of DA neurons. The generation of H2O2 by MAO induces formation of glutathione disulfide GSSG and protein-glutathione mixed disulfides PrSSG. Loss of essential protein thiol groups, such as those required by Complex I, compromises mitochondrial electron transport. In turn, mitochondrial dysfunction contributes to the progression of Parkinsons disease and to the damaging effects of environmental neurotoxins. In year 1, we showed that MAO suppressed respiration electron transport, and elevated mitochondrial PrSSG. Work in 2nd year verified the - pivotal role of 11202 and showed for the first time that pyruvate dehydrogenase PDH is also detrimentally affected by MAO. And most important, reversal of damage by pyruvate or succinate was accompanied by removal of PrSSG from the inner mitochondrial membrane. These results support the working hypothesis and help to clarify the pathophysiology of neurodegenerative mechanisms affecting DA neurons. Over the longer range, the new leads concerning a the thiol redox state of mitochondria and b mechanisms that reverse damage, can lead to improved methods to protect DA neurons from environmental neurotoxins and from the ravages of Parkinsons disease.