A role for the mitochondrial effects of the neurotransmitter serotonin in the facilitation of stress adaptation has been identified in new research. Mitochondria in neurons are the powerhouses that generate energy to execute cellular functions and regulate neuronal survival under conditions of stress.

The collaborative research, conducted by Prof. Vidita Vaidya and Prof. Ullas Kolthur-Seetharam groups at the Tata Institute of Fundamental Research in India, along with Dr. Ashok Vaidya, at Medical Research Centre, Kasturba Health Society, has demonstrated an unusual function for serotonin - in the process called mitochondrial biogenesis - in neurons, accompanied by increase in cellular respiration and ATP, the energy currency of the cell.

Mitochondrial biogenesis is the process by which cells increase mitochondrial mass. It is activated by numerous different signals during times of cellular stress. The capacity for mitochondrial biogenesis has been shown to decrease with age, and such decreased mitochondrial function has been associated with diabetes and cardiovascular disease.

[caption id="attachment_98819” align="aligncenter” width="680”]5-HT effects on mitochondrial biogenesis Schematic depicting the putative mechanism for 5-HT effects on mitochondrial biogenesis and function.
The model depicts 5-HT binding to the 5-HT2A receptor expressed by cortical neurons, which evokes an activation of the PLC and MAPK signaling pathways. This recruitment of PLC and MAPK signaling, likely through a multiple-step process, results in recruitment of SIRT1, which is a key regulator of mitochondrial biogenesis.
SIRT1 may then modulate PGC-1α expression, which has been shown to be a master regulator of mitochondrial biogenesis and, in turn, could enhance NRF1 and mitochondrial transcription factor TFAM expression, thus mediating effects of 5-HT on mitochondrial biogenesis.
Credit: Credit: Sashaina E. Fanibunda, et al[/caption]

The factors that influence mitochondrial biogenesis and function in neurons have remained poorly understood.

Master Regulators

These effects of serotonin involve the serotonin2A receptor and master regulators of mitochondrial biogenesis, SIRT1 and PGC-1α. Serotonin reduces toxic reactive oxygen species in neurons, boosts anti-oxidant enzymes and buffers neurons from the damaging effects of cellular stress.

The findings uncover an unprecedented role for serotonin in energy production in neurons directly impacting how neurons handle stress. Mitochondrial function in neurons is vital in determining how neurons cope with stress and the trajectory of aging.

Direct infusion of serotonin (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.

The work provides exciting evidence that the neurotransmitter serotonin can directly influence neuronal powerplants, thus impacting the manner in which neurons grapple with stress. This work identifies novel drug targets for treating mitochondrial dysfunction in neurons, with therapeutic potential for neurodegenerative and psychiatric disorders.

Sashaina E. Fanibunda, Sukrita Deb, Babukrishna Maniyadath, Praachi Tiwari, Utkarsha Ghai, Samir Gupta, Dwight Figueiredo, Noelia Weisstaub, Jay A. Gingrich, Ashok D. B. Vaidya, Ullas Kolthur-Seetharam, Vidita A. Vaidya Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1–PGC-1α axis Proceedings of the National Academy of Sciences May 2019, 201821332; DOI: 10.1073/pnas.1821332116

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