TIFR researchers discover a novel function of serotonin

(From left) Vidita Vaidya, Ashok Vaidya, Sashaina Fanibunda, and Ullas Kolthur-Seetharam (2)-Optimized

(From left) Vidita Vaidya, Ashok Vaidya, Sashaina Fanibunda, and Ullas Kolthur-Seetharam

In a surprising discovery, TIFR researchers have found a novel function for serotonin — generation of new mitochondria in neurons, increased cellular respiration and ATP production. The team found that serotonin reduces reactive oxygen species, thus providing neuroprotection against cellular stress.

In a surprising discovery, researchers at the Tata Institute of Fundamental Research (TIFR) Mumbai have found a novel function for serotonin (a chemical that signals between neurons). The recent discovery establishes that serotonin is involved in the generation of new mitochondria (the powerhouse of the cell) in neurons, increased cellular respiration and fuel (ATP) in the cell. Serotonin’s newly identified function has been studied in mice and rats. If found to be true in humans, which is likely to be the case, it might have important medical implications.

“We cultured neurons and looked at the effects after adding serotonin, and found really unexpected results. We knew we had stumbled on something very interesting. These finds were confirmed and validated through extensive experiments,” Prof. Vidita A Vaidya from TIFR recalls. The results of the study were published in the journal Proceedings of the National Academy of Sciences (PNAS).

At the level of an organism, serotonin is known to be involved in coping with stress. However, the underlying mechanism of its neuroprotective role was unknown. The team jointly led by Prof. Vaidya and Prof. Ullas Kolthur-Seetharam from TIFR, in collaboration with Dr. Ashok Vaidya from KHS, provides insights into how serotonin generates more mitochondria thereby giving neurons the capacity to produce more energy and the ability to cope with stress significantly better.

More than three decades ago researchers had speculated that serotonin could have antioxidant-like effects. But this was not experimentally proved. “We found that serotonin reduces reactive oxygen species, thus providing neuroprotection against cellular stress. Serotonin can impact the manner in which neurons grapple with stress and affect the trajectory of ageing,” says Prof. Vaidya.

Neuronal loss is a major cause of neurodegenerative diseases such as in Alzheimer’s and Parkinson’s. Abnormal mitochondrial functions are known to cause or contribute to neuronal death. The new findings from TIFR raise the possibility that serotonin signalling could be used to prevent mitochondrial abnormalities and neuronal loss.

Unlike other cells, neurons are not generated continuously and so identifying factors that increase mitochondrial health is key to prevent ageing-associated neurological diseases.

Experimental proof

“Neurons exposed to serotonin not only produced more fuel (ATP), even the efficiency of mitochondrial output in these neurons was higher,” says Prof. Kolthur-Seetharam, joint senior author of the paper. This was seen in experiments done both in tissue culture and rats/mice.

Neurons have 14 receptors for serotonin, but only when serotonin binds to a specific receptor (5-HT2A) does it activate SIRT1 (a very important particular longevity factor/gene) that produces new mitochondria and more ATP in neurons.  “The link between serotonin and SIRT1 protein was never made before and their interaction was essential for mitochondrial effects in neurons,” says Prof. Vaidya.

“Under in vitro conditions, neurons treated with a drug to block the 5-HT2A receptor as well as neurons that lacked the receptor abolished all the beneficial effects of serotonin on mitochondria. Further, in rats, activating the receptor using a drug enhanced the mitochondrial function,” says Dr. Sashaina Fanibunda from TIFR and first author of the paper.

When mutant mice that did not have the SIRT1 protein in the cortex were used, stimulating the 5-HT2A receptor did not lead to enhanced mitochondrial function.

Injecting serotonin directly into the brain of rats led to direct increase in mitochondria number and ATP level. Beneficial effects of serotonin were seen by genetically increasing it in the brain of 13- to 15-month-old mice. “With age, levels of serotonin, SIRT1 and mitochondria go down; the function of mitochondria also goes down. Thus supplying more serotonin could restore mitochondrial functions even in old mice,” says Prof. Kolthur-Seetharam.

“This study paves way for further research into designing novel therapeutic interventions by combined activation of serotonin and SIRT1 either through pharmacological approaches or coupling approved drugs that activate serotonin signalling with dietary interventions like calorie restriction. This may enable in tackling mood disorders and age-associated neurological decline, better,” says Prof. Kolthur-Seetharam.

Published in The Hindu on May 7, 2019