Serotonin regulation of mitochondria in kidney diseases

Abstract

Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored.

Keywords: 5-HT(1F); Kidney; Kidney disease; Mitochondria; Mitochondrial biogenesis; Serotonin.

Fig. 1.. Serotonin synthesis.

Serotonin synthesis begins with the conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase 1/2 (TPH 1/2). TPH1 is commonly expressed in the CNS, pineal gland, thymus, spleen, and gastrointestinal tract. TPH2 is more exclusively expressed in the brain stem. 5-HTP is then reduced by aromatic L-amino acid decarboxylase into serotonin.

Fig. 2.

Serotonin in the kidney. Serotonin physiologically increases glomerular filtration by increasing blood flow and vasoconstriction and increases sodium ion excretions. 5-HT activation induces MB in the proximal tubule.

Fig. 3.

Mitochondrial dysfunction in kidney diseases. Under physiological conditions, mitochondria regulate many cellular processes, such as the production of ATP, calcium homeostasis, mitochondrial quality control mechanisms, redox buffering, and programmed apoptosis. Many, if not all, of these cellular functions are disrupted during injury or disease, ultimately impairing cell and organ function.

Fig. 4.

Mitochondrial quality control mechanisms. Mitochondrial homeostasis is governed by three major mechanisms: MB, mitochondrial dynamics (fission and fusion), and mitophagy. MB is normally initiated by activation of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) via deacetylation by sirtuin1 (SIRT1) or phosphorylation by AMP-activated protein kinase (AMPK). Activation of PGC-1α results in increased mitochondrial transcription factor A (TFAM) and subsequently increased MB. Mitochondrial dynamics consists of two main processes: mitochondrial fusion and fission. Mitochondrial fusion is governed by mitofusins 1/2 (Mfn1/2) and optic atrophy-1 (OPA1). Mitochondrial fission is modulated by dynamin-related protein 1 (DRP1). Mitophagy is a selective version of autophagy for mitochondria and is characterized by accumulation of PTEN-induced kinase 1 (PINK1) and PARKIN on the outer membrane of damaged or redundant mitochondria that, with the help of sequestosome-1 (SQSTM1/P62) and microtubule-associated proteins 1A/1B light chain 3B (LC3B), which promote the engulfment of mitochondria.

Fig. 5.

5-HT receptor-mediated mitochondrial biogenesis. While the pathway is not fully known, activation of the 5-HT_2C receptor increases peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1α resulting in MB. Activation of the 5-HT_1F receptor induces a classical phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway that translocates PGC-1α into the nucleus and increases transcription of mitochondrial factors that cause MB, while simultaneously initiating an inhibitory Gβγ-dependent decreased phosphorylation of extracellular signal regulated kinases (ERK1/2) and foxhead box O3a (FOXO3a), decreasing an inhibitory MB pathway. Activation of the 5-HT_2A receptor increases the deacetylation of PGC-1α, thereby increasing its activity and inducing MB.