5-HT3 Receptors on Mitochondria Influence Mitochondrial Function

Abstract

The 5-hydroxytryptamine 3 (5-HT3) receptor belongs to the pentameric ligand-gated cation channel superfamily. Humans have five different 5-HT3 receptor subunits: A to E. The 5-HT3 receptors are located on the cell membrane, but a previous study suggested that mitochondria could also contain A subunits. In this article, we explored the distribution of 5-HT3 receptor subunits in intracellular and cell-free mitochondria. Organelle prediction software supported the localization of the A and E subunits on the inner membrane of the mitochondria. We transiently transfected HEK293T cells that do not natively express the 5-HT3 receptor with an epitope and fluorescent protein-tagged 5HT3A and 5HT3E subunits. Fluorescence microscopy and cell fractionation indicated that both subunits, A and E, localized to the mitochondria, while transmission electron microscopy revealed the location of the subunits on the mitochondrial inner membrane, where they could form heteromeric complexes. Cell-free mitochondria isolated from cell culture media colocalized with the fluorescent signal for A subunits. The presence of A and E subunits influenced changes in the membrane potential and mitochondrial oxygen consumption rates upon exposure to serotonin; this was inhibited by pre-treatment with ondansetron. Therefore, it is likely that the 5-HT3 receptors present on mitochondria directly impact mitochondrial function and that this may have therapeutic implications.

Metabolic control of induced pluripotency

“…Removing TPH2 function during the entire reprogramming process majorly enhances the efficiency of iPSC generation, while TPH2 induction suppresses the process, indicating the importance of tryptophan pool or serotonin signaling in pluripotency acquisition (Sinenko et al, 2023). The latter possibility is supported by the observed activity of serotonin in the positive regulation of mitochondrial functions and biogenesis (Fanibunda et al, 2019;Rao et al, 2023). It has also been shown that a key enzyme in glycine degradation, glycine decarboxylase (GLDC), is involved in the early stages of cell reprogramming (Kang et al, 2019).…”