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

Abstract

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.

Mitochondrial function in the brain links anxiety with social subordination

“…Among the possible mechanisms involved, it is tempting to consider the participation of the dopaminergic system as several studies have linked high dopamine levels with reduced mitochondrial capacity in cells (49,50). As we found activation of D1-containing cells following social competition, it is possible that differences in dopamine, as a function of anxiety, could contribute to the observed differences in mitochondrial function.…”

Mitochondrial oxidative stress induced by Ca2+ and monoamines: different behaviour of liver and brain mitochondria in undergoing permeability transition

“…and phosphate in RLM (Marcocci et al 2002). The dopamine reaction product, dopaquinone, showed similar effects (Bisaglia et al 2010), while in other studies, dopamine appears not amplifying the MPT (Brenner-Lavie et al 2008). These studies demonstrate the lack of a clear and common mechanism in response to monoamines in the different types of mitochondria.…”

“…These studies concerned principally the action of the natural polyamines (Sava et al 2006;Toninello et al 2004), but also that of the propargylamines (Marcocci et al 2002) and diamines, in particular agmatine (Battaglia et al 2007). As far as the monoamines are concerned, only tyramine and dopamine have been investigated as MPT inducers in RLM (Marcocci et al 2002, Brenner-Lavie et al 2008). …”

The role of mitochondrial dysfunction in psychiatric disease

“…All of these mechanisms could eventually lead to structural remodeling and long-term changes in synaptic plasticity [Smythies, 1999]. Dysfunction of dopamine metabolism, storage, release, or uptake mechanisms in the mesolimbic systems seems to occur in schizophrenia [Laruelle et al, 1999], and a wide range of data suggests that dopamine can inhibit the mitochondrial respiratory system and, in particular, complex I [Brenner-Lavie et al, 2008].…”