The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner

Abstract

Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin(5-HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti-depressant drug. Human allelic variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) such as the S/S variant, are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using a rat model that is haploinsufficient for SERT and displays reduced SERT expression similar to the human S/S variant, we demonstrate that reduced SERT expression modulates mitochondrial copy number and expression of respiratory chain electron transfer components in the brain. In the frontal cortex, genotype-related trends were opposing for males and females, such that reduced SERT expression led to increased expression of the Complex I subunit mt-Nd1 in males but reduced expression in females. Our findings suggest that SERT expression and serotonergic signaling have a role in regulating mitochondrial biogenesis and adenosine triphosphate (ATP) production in the brain. We speculate that the sexual dimorphism in mitochondrial abundance and gene expression contributes to the sex bias found in the incidence of neuropsychiatric disorders such as MDD and ASD.

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

“…However, it is important to note that all these previous studies were performed in male rats only. A recent review highlights the heavy sex bias in SERT research which has worsened since the turn of the millennium (Thorne et al 2022b ). Therefore, this study provides further justification to include females in order to get a full picture of the role of the SERT in drug addiction, particularly given the variability in human studies described in the introduction.…”

Mitochondrial Interaction with Serotonin in Neurobiology and Its Implication in Alzheimer’s Disease

“…Additionally, the influence of the SERT on mitochondria has been reported [55]. A previous study showed a negative correlation between SERT expression and mitochondrial copy number in the brains of male rats, while reduced SERT expression led to a decrease in mitochondrial copy number in females [55]. Regardless of the unclear mechanisms underlying the impact of SERT on mitochondria and the sex-related dimorphic regulation, these findings implicate the involvement of serotonin signaling in mitochondrial biology.…”

“…This suggests that the role of serotonin in regulating mitochondria is not exclusive to neural cells. Additionally, the influence of the SERT on mitochondria has been reported [55]. A previous study showed a negative correlation between SERT expression and mitochondrial copy number in the brains of male rats, while reduced SERT expression led to a decrease in mitochondrial copy number in females [55].…”

Neuroplasticity of children in autism spectrum disorder

“…Patients with ASD often exhibit hyper-serotonemia, and 5-HT levels are significantly predictive of ASD development ( 65 ). Its receptor serotonin transporter protein (SERT) was found to regulate synaptic serotonin, modulating mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner, which could help explain the gender bias in ASD prevalence ( 66 ). Catecholamines are neurotrophic and regulatory factors, with DA primarily responsible for attention, reward motivation, motor and communication skills ( 67 ).…”