Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis.

The neurotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is closely linked to mitochondrial abnormalities while mitophagy is vital for mitochondrial homeostasis. However, whether PBDE-47 disrupts mitophagy contributing to impaired neurodevelopment remain elusive. Here, this study showed that neonatal PBDE-47 exposure caused learning and memory deficits in adult rats, accompanied with striatal mitochondrial abnormalities, neuronal apoptosis and the resultant neuronal loss. Mechanistically, PBDE-47 suppressed PINK1/Parkin-mediated mitophagy induction and degradation, inducing mitophagosome accumulation and mitochondrial dysfunction in vivo and in vitro. Additionally, stimulation of mitophagy by adenovirus-mediated Parkin or Autophagy-related protein 7 (Atg7) overexpression aggravated PBDE-47-induced mitophagosome accumulation, mitochondrial dysfunction, neuronal apoptosis and death. Conversely, suppression of mitophagy by the siRNA knockdown of Atg7 rescued PBDE-47-induced detrimental consequences. Importantly, melatonin, a hormone secreted rhythmically by the pineal, improved PBDE-47-caused neurotoxicity via preventing neuronal apoptosis and loss by restoring mitophagic activity and mitochondrial function. These neuroprotective effects of melatonin depended on activation of the AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) signaling. Collectively, these data indicate that PBDE-47 impairs mitophagy to perturb mitochondrial homeostasis, thus triggering apoptosis, leading to neuronal loss and consequent neurobehavioral deficits. Manipulation of the AMPK-mitophagy axis via melatonin could be a novel therapeutic strategy against developmental PBDE-47 neurotoxicity. © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

Lixin Dong, Qian Sun, Haixia Qiu, Kaichao Yang, Boya Xiao, Tao Xia, Aiguo Wang, Hui Gao, Shun Zhang. Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis. Journal of pineal research. 2023 Aug;75(1):e12871

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PMID: 37042059

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