Serotonin, a phylogenetically ancient molecule that predates the evolution of the nervous system, was likely co-opted to function as a neurotransmitter. Serotonin retains “pre-nervous” trophic-factor actions influencing development and growth, while exerting pleiotropic neurotransmitter effects on diverse brain functions and behavior [1]. Serotonin is speculated to exert antioxidant-like actions [1]; however, its influence on the energy producing organelle, mitochondria, and on a neuron’s stress buffering capacity remains poorly understood.

Mitochondrial function is essential to fulfill substantial neuronal metabolic demands, maintain excitability, and facilitate synaptic transmission. Mitochondria serve as key signaling platforms, coupling metabolic status to mitochondrial dynamics, biogenesis and function, and influence neuronal metabolism, intracellular signaling, and synaptic plasticity [2]. Mitochondrial biogenesis is an adaptive mechanism that responds to cellular energetic demands and oxidative insults, and can promote neuronal viability. We hypothesized that serotonin in keeping with its putative trophic and antioxidant-like actions, may serve as an upstream modulator of mitochondria in neurons and thus influence stress buffering.

Our study demonstrates that serotonin, via the serotonin2A receptor, enhances mitochondrial biogenesis in rodent cortical neurons, increases mitochondrial function, respiratory capacity, and ATP generation [3]. These intriguing effects arise via recruitment of master modulators of mitochondrial biogenesis, the sirtuin SIRT1, and the transcriptional coactivator PGC-1α, that are strongly implicated in metabolic control and longevity. Serotonin infusion or chemogenetic activation of endogenous serotonin release increased neocortical mitochondrial mass and function. The serotonin-mediated increase in respiration and ATP production is not simply a consequence of greater mitochondrial mass, but also reflects improved OxPhos efficiency per mitochondrion. Our study identifies the serotonin2A receptor-SIRT1-PGC-1α axis as a putative target to enhance neuronal mitochondrial function. The influence of serotonin on mitochondria likely extends beyond neurons, as serotonin1F and serotonin2A/2C receptors enhance renal mitochondrial biogenesis [4], and serotonin2B receptors modulate cardiomyocyte mitochondrial structure/function [5].

Serotonin reduces cellular reactive oxygen species (ROS), upregulates ROS scavenging enzymes, and profoundly enhances neuronal survival of cortical neurons challenged with oxidative and excitotoxic stress. The prosurvival effects of serotonin are mediated via the serotonin2A receptor and require SIRT1 [3]. This link between serotonin, bioenergetics, and neuronal survival provides a new framework for how serotonin signaling impacts stress responses, both at a cellular and organismal level. Our study motivates further investigation to address the contribution of mitochondrial modulation to the effects of serotonin on mood regulation, neuroplasticity, and senescence.

Mitochondria have recently emerged as important targets to consider both from the perspective of pathogenesis and treatment of psychiatric disorders [6]. Mitochondria contribute to the buffering of stress-associated allostatic load, and mitochondrial dysfunction can hamper stress-adaptation and enhance risk for psychopathology [2]. Mounting evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can impact mitochondrial function; however, these effects vary based on the SSRI utilized, motivating a systematic examination of the influence of SSRIs on mitochondrial biogenesis, dynamics, and function. Our findings uncover a pathway linking serotonin, via the metabolism and longevity-associated sirtuin, SIRT1, to neuronal survival and the amelioration of mitochondrial dysfunction, with important implications for both neurodegenerative and neuropsychiatric diseases.

Funding and disclosure

This work was funded by the Tata Institute of Fundamental Research, Department of Atomic Energy, Government of India, under project no. RTI4003. The authors declare no competing interests.