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

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Mitochondrial homeostasis is crucial for neuronal function, with mitophagy playing a key role.
• 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) is a flame retardant linked to neurotoxicity and mitochondrial dysfunction.
• The specific impact of PBDE-47 on mitophagy and subsequent neurodevelopmental outcomes remains unclear.

Purpose of the Study:

• To investigate whether PBDE-47 disrupts mitophagy, contributing to neurodevelopmental deficits.
• To elucidate the underlying molecular mechanisms of PBDE-47-induced neurotoxicity.
• To explore the therapeutic potential of melatonin in mitigating PBDE-47 neurotoxicity.

Main Methods:

• Neonatal rats were exposed to PBDE-47, followed by behavioral assessments and biochemical analyses.
• In vitro and in vivo studies examined the effects of PBDE-47 on mitophagy pathways (PINK1/Parkin, Atg7).
• Adenovirus-mediated gene overexpression and siRNA knockdown were used to manipulate mitophagy.
• Melatonin treatment was administered to assess its neuroprotective effects and underlying signaling pathways (AMPK/ULK1).

Main Results:

• PBDE-47 exposure induced learning and memory deficits, striatal mitochondrial abnormalities, and neuronal apoptosis.
• PBDE-47 suppressed PINK1/Parkin-mediated mitophagy, leading to mitophagosome accumulation and mitochondrial dysfunction.
• Melatonin treatment ameliorated PBDE-47-induced neurotoxicity by restoring mitophagy and mitochondrial function via AMPK/ULK1 activation.

Conclusions:

• PBDE-47 impairs mitophagy, disrupting mitochondrial homeostasis and causing neurobehavioral deficits.
• Melatonin exhibits neuroprotective effects against developmental PBDE-47 toxicity by modulating the AMPK-mitophagy axis.
• Targeting the AMPK-mitophagy pathway with melatonin represents a potential therapeutic strategy for PBDE-47 neurotoxicity.