Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT

Significance Neuronal mitochondria are crucial organelles that regulate bioenergetics and also modulate survival and function under environmental challenges. Here, we show that the neurotransmitter serotonin (5-HT) plays an important role in the making of new mitochondria (mitochondrial biogenesis) in cortical neurons, through the 5-HT2A receptor and via master regulators of mitochondrial biogenesis, SIRT1 and PGC-1α. Mitochondrial function is also enhanced by 5-HT, increasing cellular respiration and ATP, the energy currency of the cell. We found 5-HT reduces cellular reactive oxygen species and exerts potent neuroprotective action in neurons challenged with stress, an effect that requires SIRT1. These findings highlight a role for the mitochondrial effects of 5-HT in the facilitation of stress adaptation and identify drug targets to ameliorate mitochondrial dysfunction in neurons.
Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1–PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.