|Ph.D Student||Brenner-Lavie Hanit|
|Subject||A Possible Linkage between Dopamine and Mitochondria|
Implications to Schizophrenia
|Department||Department of Medicine||Supervisors||Professor Dorit Ben-Shachar|
|Professor Emeritus Ehud Klein|
|Full Thesis text|
Aberration in the dopaminergic system is regarded as the predominant pathological factor in schizophrenia. Recently, dysfunction of the mitochondria in general and of mitochondrial oxidative phosphorylation system (OXPHOS) in particular, has been raised as an additional major pathology in schizophrenia. Given the important roles dopamine (DA) and mitochondria play in schizophrenia, the present study was aimed to investigate a possible interaction between both, and to elucidate the relevance of such an interaction to schizophrenia. DA, but not NE or 5-HT, significantly dissipated mitochondrial membrane potential and decreased oxygen utilization in viable human SH-SY5Y neuroblastoma cells. DA induced inhibition was dependent on the presence of dopamine transporter, prevented by cocaine and intensified by tranylcyoromine, indicating an intracellular effect of DA on mitochondrial respiration. DA induced mitochondrial dysfunction by specifically inhibiting the first complex of the OXPHOS. Interestingly, DA effect on cells respiration was not associated with ROS formation including H2O2 and superoxides. Long-term effects of DA on complex I and mitochondrial respiration were not associated with changes in mRNA and protein expression of three of complex I subunits (24kDa, 51kDa and 75kDa), which are abnormally expressed in schizophrenia. Interestingly, a pathological interaction between DA and complex I was observed in disrupted mitochondria isolated from platelets as well as in EBV transformed lymphocytes of schizophrenic patients. Further support for the involvement of DA related interaction with complex I in schizophrenia is the finding that both typical and atypical antipsychotic drugs, but not antidepressant drugs, specifically inhibit complex I activity, as well as complex I driven mitochondrial respiration. These findings suggest that in addition to DA receptors, complex I is a potential common target for DA and the antipsychotic drugs. The present study demonstrates that DA can lead to mitochondrial dysfunction by a direct inhibition of mitochondrial complex I. These findings add a novel piece of information to the puzzle of the complex picture making up the pathology of schizophrenia. We suggest that this DA-complex I interaction, which is not associated with the production of ROS, describes the pathological processes of non-degenerative disorders, such as schizophrenia better than the theory connecting DA toxicity to oxidative stress. The latter, is more likely associated with neurodegenerative processes typical of Parkinson's disease. Unfolding a link between these two major malfunctions in schizophrenia, the dopaminergic system and energy metabolism, may encourage novel treatment approaches, as well as new insights about the pathophysiology and etiology of the disorder.