Dopamine Inhibits Mitochondrial Motility in Hippocampal Neurons

Abstract

BackgroundThe trafficking of mitochondria within neurons is a highly regulated process. In an earlier study, we found that serotonin (5-HT), acting through the 5-HT1A receptor subtype, promotes axonal transport of mitochondria in cultured hippocampal neurons by increasing Akt activity, and consequently decreasing glycogen synthase kinase (GSK3β) activity. This finding suggests a critical role for neuromodulators in the regulation of mitochondrial trafficking in neurons. In the present study, we investigate the effects of a second important neuromodulator, dopamine, on mitochondrial transport in hippocampal neurons.Methodology/Principal FindingsHere, we show that dopamine, like 5-HT, regulates mitochondrial motility in cultured hippocampal neurons through the Akt-GSK3β signaling cascade. But, in contrast to the stimulatory effect of 5-HT, administration of exogenous dopamine or bromocriptine, a dopamine 2 receptor (D2R) agonist, caused an inhibition of mitochondrial movement. Moreover, pretreatment with bromocriptine blocked the stimulatory effect of 5-HT on mitochondrial movement. Conversely, in cells pretreated with 5-HT, no further increases in movement were observed after administration of haloperidol, a D2R antagonist. In contrast to the effect of the D2R agonist, addition of SKF38393, a dopamine 1 receptor (D1R) agonist, promoted mitochondrial transport, indicating that the inhibitory effect of dopamine was actually the net summation of opposing influences of the two receptor subtypes. The most pronounced effect of dopamine signals was on mitochondria that were already moving directionally. Western blot analysis revealed that treatment with either a D2R agonist or a D1R antagonist decreased Akt activity, and conversely, treatment with either a D2R antagonist or a D1R agonist increased Akt activity.Conclusions/SignificanceOur observations strongly suggest a role for both dopamine and 5-HT in regulating mitochondrial movement, and indicate that the integrated effects of these two neuromodulators may be important in determining the distribution of energy sources in neurons.

Brain-derived Neurotrophic Factor (BDNF)-induced Mitochondrial Motility Arrest and Presynaptic Docking Contribute to BDNF-enhanced Synaptic Transmission

“…It has been reported that nerve growth factor (NGF) affects mitochondrial motility by its downstream phosphoinositide 3-kinase (PI3K) signaling pathway (8). Edelman and co-workers (9,10) have demonstrated that Akt-glycogen synthase kinase 3␤ (GSK3␤) is associated with axonal mitochondrial transport stimulated by serotonin and dopamine. Calcium has been demonstrated to be one of the critical factors that regulate mitochondrial transport (11)(12)(13).…”

Mitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease

“…Dopamine also inhibited mitochondrial complex I-driven respiration when added short-term or long-term to the medium of cultured SH-SY5Y cells [213]. Moreover, administration of exogenous dopamine to hippocampal neurons blocked the trafficking of mitochondria [214]. Finally, dopamine has been shown to interfere with CMA [215] and to promote autophagy-dependent cell death via upregulation of asynuclein expression [216].…”

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