Aanat, short for arylalkylamine N-acetyltransferase, is the rate-limiting enzyme in melatonin synthesis [1,2,3,4,5,7]. It catalyzes the conversion of serotonin to N-acetyl serotonin, a key step in the melatonin biosynthesis pathway. Melatonin is intricately linked to circadian and circannual rhythms, regulating various physiological functions in mammals [2,6,7]. The Aanat gene's expression is tightly regulated, often in response to environmental lighting and neurotransmitter-mediated signaling pathways, such as those involving norepinephrine and cAMP-response element-binding protein (CREB) [2,9].

In a melatonin-deficient Aanat knockout mouse model, increased mitochondrial oxidative stress, decreased mitochondrial membrane potential, and higher mitochondrial DNA (mtDNA) release were observed in the brain and primary cerebro-cortical neurons. The released cytosolic mtDNA activated the cGAS/STING/IRF3 pathway, stimulating inflammatory cytokine generation, suggesting that Aanat deficiency may lead to an inflammatory response associated with accelerated aging and neurodegeneration [8]. Additionally, Aanat knockdown in embryos significantly impeded embryonic development, which could be rescued by melatonin supplementation. This indicates that Aanat-mediated melatonin synthesis in embryos is crucial for maintaining mitochondrial function, reducing reactive oxygen species (ROS) production, and maintaining normal DNA methylation through regulating Tet2 expression [10].

In conclusion, Aanat plays an essential role in melatonin synthesis, which is vital for maintaining normal physiological functions related to circadian rhythms, mitochondrial function, and embryonic development. The study of Aanat knockout models has provided insights into its role in neurodegeneration and embryonic development, suggesting its potential as a therapeutic target for related diseases.

References:

1. Wandrey, Nicole, Hamilton, Luke, Boley, Jake, Moxley, Michael A, Thomas, Allen A. 2024. AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs. In Bioorganic & medicinal chemistry letters, 113, 129975. doi:10.1016/j.bmcl.2024.129975. https://pubmed.ncbi.nlm.nih.gov/39332648/

2. Ho, Anthony K, Chik, Constance L. 2009. Modulation of Aanat gene transcription in the rat pineal gland. In Journal of neurochemistry, 112, 321-31. doi:10.1111/j.1471-4159.2009.06457.x. https://pubmed.ncbi.nlm.nih.gov/19860854/

3. Huang, Yen-Sung, Lo, Chang-Han, Tsai, Ping-Huang, Shih, Hsiu-Ming, Wu, Chia-Chao. 2021. Downregulation of AANAT by c-Fos in tubular epithelial cells with membranous nephropathy. In Biochemical and biophysical research communications, 584, 32-38. doi:10.1016/j.bbrc.2021.10.079. https://pubmed.ncbi.nlm.nih.gov/34763165/

4. Rios, Maximiliano N, Marchese, Natalia A, Guido, Mario E. 2023. Arylalkylamine N-acetyltransferase (AANAT): Blue light induction, nuclear translocation, and potential role in the survival of chicken retina neuronal cells. In Journal of pineal research, 75, e12875. doi:10.1111/jpi.12875. https://pubmed.ncbi.nlm.nih.gov/37070273/

5. Hagemeister, Mackenzie, Hamilton, Luke, Wandrey, Nicole, Moxley, Michael A, Thomas, Allen A. 2023. Evaluation of Rhodanine Indolinones as AANAT Inhibitors. In ChemMedChem, 19, e202300567. doi:10.1002/cmdc.202300567. https://pubmed.ncbi.nlm.nih.gov/37984928/

6. Yin, Daiqing, Zhou, RuRu, Yin, Mengxin, Xu, Shixia, Yang, Guang. . Gene Duplication and Loss of AANAT in Mammals Driven by Rhythmic Adaptations. In Molecular biology and evolution, 38, 3925-3937. doi:10.1093/molbev/msab125. https://pubmed.ncbi.nlm.nih.gov/33944919/

7. Moskaleva, P V, Shnayder, N A, Nasyrova, R F. . [Association of polymorphic variants of DDC (AADC), AANAT and ASMT genes encoding enzymes for melatonin synthesis with the higher risk of neuropsychiatric disorders]. In Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 121, 151-157. doi:10.17116/jnevro2021121041151. https://pubmed.ncbi.nlm.nih.gov/34184492/

8. Jauhari, Abhishek, Baranov, Sergei V, Suofu, Yalikun, Carlisle, Diane L, Friedlander, Robert M. . Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. In The Journal of clinical investigation, 130, 3124-3136. doi:10.1172/JCI135026. https://pubmed.ncbi.nlm.nih.gov/32182222/

9. Simonneaux, Valérie, Sinitskaya, Natalia, Salingre, Anthony, Garidou, Marie Laure, Pévet, Paul. . Rat and Syrian hamster: two models for the regulation of AANAT gene expression. In Chronobiology international, 23, 351-9. doi:. https://pubmed.ncbi.nlm.nih.gov/16687308/

10. Yang, Minghui, Tao, Jingli, Wu, Hao, Liu, Jinghao, Liu, Guoshi. 2018. Aanat Knockdown and Melatonin Supplementation in Embryo Development: Involvement of Mitochondrial Function and DNA Methylation. In Antioxidants & redox signaling, 30, 2050-2065. doi:10.1089/ars.2018.7555. https://pubmed.ncbi.nlm.nih.gov/30343588/