Mitochondria, cellular power plants, are known for their symbiotic history of origin and evolution. Recently, a three-way symbiotic interaction between laboratories from the Tata Institute of Fundamental Research (TIFR), Mumbai, and Medical Research Centre, Kasturba Health Society, Mumbai, has led to a discovery about how brain cells regulate the number and function of their mitochondria. 

Neurobiologist Vidita Vaidya is a serotonin aficionado, who studies the role of this neurotransmitter in emotional regulation. Mitochondrial biologist Ullas Kolthur-Seetharam, on the other hand, studies the role of a family of proteins called ​‘Sirtuins’ in metabolism, ageing, and cancer. Vaidya’s father, Ashok Vaidya, Research Director at Kasturba Health Society, Mumbai, is an expert on clinical pharmacology. Together, they have shown that serotonin enhances mitochondrial function in nerve cells (neurons), which may protect these cells against stress.

In 2013, the three researchers were jointly pursuing an industry-funded collaborative project on the effect of plant-derived neuroprotective compounds on neurons. Since mitochondria are crucial for the survival and function of neurons, mitochondrial levels were a good indicator of the level of neuroprotection rendered by candidate compounds. 

When they felt the need for a comparative in this study, Vaidya’s lab favourite serotonin was a logical choice as this versatile ancient compound has a significant role in brain homeostasis. Surprisingly, the researchers found that serotonin significantly enhanced the level of ATP – the energy currency of the cell – generated primarily in mitochondria. 

Upon testing other neurotransmitters like dopamine or norepinephrine or neuronal stimulants like potassium chloride, the researchers found that this observation was specific to serotonin. Cells treated with serotonin also showed an increase in the levels of markers like mitochondrial DNA and mitochondrial proteins, all of which pointed towards an increase in mitochondria.

“So at this point, we realised that we have stumbled on something,” says Vidita. The team went on to study this process systematically using multiple approaches and controls. The studies began in vitro (in cultured cells), but several of the observations were also confirmed in vivo (in mice).

Previous studies from Kolthur-Seetharam’s group and others in the field have noted that Sirt1, a nuclear protein of the Sirtuin family, is crucial for mitochondrial function. The researchers found that when serotonin binds one of its receptors (5‑HT_2A) on the neurons, it leads to a signalling cascade which recruits Sirt1. Sirt1, in turn, induces the synthesis of more mitochondria and increases cellular energy levels. At the same time, levels of antioxidant enzymes in the neurons rise, potentially providing protection against cellular stress. 

Even with their own DNA, mitochondria are not fully autonomous as they depend on proteins encoded by nuclear DNA. Given that Sirt1 is a nuclear protein, Kolthur-Seetharam mentions that it is fascinating to understand the crosstalk between two key organelles (mitochondria and nucleus) with genetic information cohabiting a cell. He believes that through its regulation by serotonin, Sirt1 is serving as a metabolic sensor in this dialogue. 

Mitochondrial levels and function are known to decline in mood disorders, with age, or in neurodegenerative disorders like Alzheimer’s disease. This is often characterized by a decrease in energy levels (ATP) and an increase in cellular stress. Based on this study, the researchers suggest that the serotonin receptor 5‑HT_2A could become a potential drug target. 

Vaishnavi Ananthanarayanan, Assistant Professor, Indian Institute of Science, Bangalore, suggests another potential application for this study. ​“Gastrointestinal (GI) tract also produces serotonin,” she points out. GI disorders such as irritable bowel syndrome (IBD) frequently accompany mood disorders. 

Intriguingly, the intestinal cells of patients with IBD also exhibit dysfunctional mitochondria. ​“This study could potentially lead to a better understanding of the link between mood disorders and GI issues in the context of mitochondrial dysfunction,” says Ananthanarayanan.

Talking about experimental challenges, Sashaina Fanibunda, the first author of the study, mentions that setting up the in vitro culture system was often challenging and getting sufficient material to do an experiment was difficult. According to her, ​“The most challenging part of this study were the experiments that Babukrishna Maniyadath (another author) and I performed together, to isolate mitochondria from the cortex…and keeping these healthy and alive.”

The study is also an example of a father-daughter symbiosis. ​“Working with my father was very enjoyable and of course a rare opportunity,” says Vidita, ​“His unusual mind and clinical insight was very helpful to design several experiments or interpret the results.” 

Fanibunda explains how the three-way collaboration unfolded over the years. ​“We would meet in our lab, in our little hut by the sea, on Thursdays once or twice a month. It was interesting to see how each one tackled the same problem from different angles,” she says, crediting their success to these discussions and brainstorming sessions in. 

The study also involved collaborators from Favaloro University, Argentina and Columbia University, New York, who provided essential reagents and mouse lines.

“Besides a collaborative bent of mind, one needs to put science before people to get past the issues like taking credit or sharing of reagents,” says Kolthur-Seetharam.

Both Vaidya and Kolthur-Seetharam emphasise scientific openness, constructive criticism, and generous sharing as the basis of their successful alliance so far. The trio will continue their collaboration and keep gaining from their complementary skills and thoughts.

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