粒体自噬
帕金
神经毒性
品脱1
安普克
细胞生物学
神经保护
褪黑素
自噬
线粒体
生物
程序性细胞死亡
内分泌学
细胞凋亡
内科学
蛋白激酶A
激酶
神经科学
医学
生物化学
帕金森病
毒性
疾病
作者
Lanlan Dong,Qian Sun,H.Y. Qiu,Kaichao Yang,Boya Xiao,Xiaolan Jiang,Aiguo Wang,Hui Gao,Shun Zhang
摘要
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.
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