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

Abstract

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.

Medical Prospect of Melatonin in the Intervertebral Disc Degeneration through Inhibiting M1-Type Macrophage Polarization via SIRT1/Notch Signaling Pathway

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The potential influence of melatonin on mitochondrial quality control: a review

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Ruthenium-Anchored Carbon Sphere-Customized Sensor for the Selective Amperometric Detection of Melatonin

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