Effects of melatonin on dopaminergic neuron development via IP3-mediated mitochondrial Ca2+ regulation in autism spectrum disorder

Shuangshan Dong; Takashi Kifune; Hiroki Kato; Lu Wang; Jun Kong; Yuta Hirofuji; Xiao Sun; Hiroshi Sato; Yosuke Ito; Takahiro A Kato; Yasunari Sakai; Shouichi Ohga; Satoshi Fukumoto; Keiji Masuda

doi:10.1016/j.bbrc.2023.09.050

Effects of melatonin on dopaminergic neuron development via IP3-mediated mitochondrial Ca²⁺ regulation in autism spectrum disorder

Biochem Biophys Res Commun. 2023 Nov 12:681:7-12. doi: 10.1016/j.bbrc.2023.09.050. Epub 2023 Sep 19.

Authors

Affiliations

¹ Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
² Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
³ Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
⁴ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan.
⁵ Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan. Electronic address: fukumoto@dent.kyushu-u.ac.jp.
⁶ Section of Oral Medicine for Children, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka, 812-8582, Japan. Electronic address: kemasuda@dent.kyushu-u.ac.jp.

PMID: 37742475
DOI: 10.1016/j.bbrc.2023.09.050

Abstract

Melatonin entrainment of suprachiasmatic nucleus-regulating circadian rhythms is mediated by MT1 and MT2 receptors. Melatonin also has neuroprotective and mitochondrial activating effects, suggesting it may affect neurodevelopment. We studied melatonin's pharmacological effects on autism spectrum disorder (ASD) neuropathology. Deciduous tooth-derived stem cells from children with ASD were used to model neurodevelopmental defects and differentiated into dopaminergic neurons (ASD-DNs) with or without melatonin. Without melatonin, ASD-DNs had reduced neurite outgrowth, mitochondrial dysfunction, lower mitochondrial Ca²⁺ levels, and Ca²⁺ accumulation in the endoplasmic reticulum (ER) compared to control DNs from typically developing children-derived stem cells. Melatonin enhanced IP3-dependent Ca²⁺ release from ER to mitochondria, improving mitochondrial function and neurite outgrowth in ASD-DNs. Luzindole, an MT1/MT2 antagonist, blocked these effects. Thus, melatonin supplementation may improve dopaminergic system development in ASD by modulating mitochondrial Ca²⁺ homeostasis via MT1/MT2 receptors.

Keywords: Autism spectrum disorder; Calcium; Melatonin; Mitochondria; Neurodevelopment.