Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia.

BACKGROUND: Mitochondria have been suggested to be involved in the pathology of bipolar disorder (BD) and schizophrenia. However, the mechanism underlying mitochondrial dysfunction is unclear. Mitochondrial network dynamics, which reflects cellular metabolic state, is important for embryonic development, synapse formation, and neurodegeneration. This study aimed to investigate mitochondrial network dynamics and its plausible association with abnormal cellular oxygen consumption in schizophrenia. METHODS: Viable Epstein-Barr virus (EBV)-transformed lymphocytes (lymphoblastoids) from DSM-IV diagnosed patients with schizophrenia (n = 17), BD (n = 15), and healthy control subjects (n = 15) were assessed for mitochondrial respiration, mitochondrial dynamics, and relevant protein levels by oxygraph, confocal microscopy, and immunoblotting, respectively. RESULTS: Respiration of schizophrenia-derived lymphoblastoids was significantly lower compared with control subjects, and was twice as sensitive to dopamine (DA)-induced inhibition. Unlike DA, haloperidol inhibited complex I-driven respiration to a similar extent in both schizophrenia and the control cells. Both drugs interact with complex I but at different sites. At the site of DA interaction, we found alterations in protein levels of three subunits of complex I in schizophrenia. In addition, we observed structural and connectivity perturbations in the mitochondrial network, associated with alterations in the profusion protein OPA1, which was similarly reduced in schizophrenia prefrontal cortex specimens. None of these alterations were observed in the BD cells, which were similar to control cells. CONCLUSIONS: We show impaired mitochondrial network dynamics associated with reduced cellular respiration and complex I abnormalities in schizophrenia but not in BD. If these findings represent disease-specific alterations, they may become an endophenotype biomarker for schizophrenia.

Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells.

Accumulating evidence suggests a role for mitochondria in synaptic potentiation and neurotransmission as well as in morphogenesis and plasticity of spines and synapses. However, studies investigating the ability of neurotransmitters to reciprocally affect mitochondrial function are sparse. In the present study we investigated whether dopamine can affect mitochondrial function in intact neuronal cells. We have shown that short- or long-term exposure of human neuroblastoma SH-SY5Y cells to dopamine (DA) inhibited mitochondrial respiration. This inhibition was associated with an increase in DA intracellular levels, and was prevented by the DA membrane transporter inhibitors, cocaine and GBR-12909. DA inhibited respiration driven through complex I but not through complexes II or III, in line with DA ability to specifically inhibit complex I activity in mitochondrial preparations. The effect of DA on complex I was not associated with altered expression of three subunits of complex I, which were formerly reported abnormal in DA-related pathologies. DA effects on respiration were not due to its ability to form reactive oxygen species. Antipsychotic drugs, which compete with DA on its receptors and inhibit complex I activity, also decreased complex I driven mitochondrial respiration. These findings may suggest that DA, which is taken up by neurons, can affect mitochondria and thereby neurotransmission and synaptic plasticity. Such a mechanism may be of relevance to DA-related non-degenerative pathologies such as schizophrenia.

Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia.

Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson's disease. DA detrimental effects have been attributed to its ability to be auto-oxidized to toxic reactive oxygen species. Since, unlike Parkinson's disease, schizophrenia does not involve neurodegenerative processes, we suggest a novel mechanism by which DA impairs mitochondrial function without affecting cell viability. DA significantly dissipated mitochondrial membrane potential (delta psi m) in SH-SY5Y cells. Bypassing complex I prevented the DA-induced depolarization. Moreover, DA inhibited complex I but not complex II activity in disrupted mitochondria, suggesting complex I participation in DA-induced mitochondrial dysfunction. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent Km=122.1+/-28.6 nM and Vmax=1.41+/-0.15 pmol/mg protein/min, thereby enabling the interaction between DA and complex I. DA accumulation was an energy and Na+-dependent process. The pharmacological profile of mitochondrial DA uptake differed from that of other characterized DA transporters. Finally, relevance to schizophrenia is demonstrated by an abnormal interaction between DA and complex I in schizophrenic patients. These results suggest a non-lethal interaction between DA and mitochondria possibly via complex I, which can better explain DA-related pathological processes observed in non-degenerative disorders, such as schizophrenia.