RGD Reference Report - Melatonin protects against developmental PBDE-47 neurotoxicity by targeting the AMPK/mitophagy axis. - Rat Genome Database

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

Authors: Dong, Lixin  Sun, Qian  Qiu, Haixia  Yang, Kaichao  Xiao, Boya  Xia, Tao  Wang, Aiguo  Gao, Hui  Zhang, Shun 
Citation: Dong L, etal., J Pineal Res. 2023 Aug;75(1):e12871. doi: 10.1111/jpi.12871. Epub 2023 Apr 27.
RGD ID: 407532700
Pubmed: PMID:37042059   (View Abstract at PubMed)
DOI: DOI:10.1111/jpi.12871   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Atg7Ratpositive regulation of mitophagy  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atg7  (autophagy related 7)

Objects referenced in this article
Gene Atg16l1 autophagy related 16-like 1 Rattus norvegicus

Additional Information