Atox1 protects hippocampal neurons after traumatic brain injury via DJ-1 mediated anti-oxidative stress and mitophagy
Pengzhan Zhao,
Wenqian Shi,
Yangfan Ye,
Ke Xu,
Jingming Hu,
Honglu Chao,
ZeQiang Tao,
Lei Xu,
Wei Gu,
Liuchao Zhang,
Tian Wang,
Xinyue Wang,
Jing Ji
Affiliations
Pengzhan Zhao
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Wenqian Shi
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Yangfan Ye
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Ke Xu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Jingming Hu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Honglu Chao
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
ZeQiang Tao
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Lei Xu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Wei Gu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Liuchao Zhang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Tian Wang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Xinyue Wang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Jing Ji
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China; Department of Neurosurgery, The Affiliated Kizilsu Kirghiz Autonomous Prefecture People's Hospital of Nanjing Medical University, Artux, Xinjiang, China; Corresponding author. Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
Regulation of the oxidative stress response is crucial for the management and prognosis of traumatic brain injury (TBI). The copper chaperone Antioxidant 1 (Atox1) plays a crucial role in regulating intracellular copper ion balance and impacting the antioxidant capacity of mitochondria, as well as the oxidative stress state of cells. However, it remains unknown whether Atox1 is involved in modulating oxidative stress following TBI. Here, we investigated the regulatory role of Atox1 in oxidative stress on neurons both in vivo and in vitro, and elucidated the underlying mechanism through culturing hippocampal HT-22 cells with Atox1 mutation. The expression of Atox1 was significantly diminished following TBI, while mice with overexpressed Atox1 exhibited a more preserved hippocampal structure and reduced levels of oxidative stress post-TBI. Furthermore, the mice displayed notable impairments in learning and memory functions after TBI, which were ameliorated by the overexpression of Atox1. In the stretch injury model of HT-22 cells, overexpression of Atox1 mitigated oxidative stress by preserving the normal morphology and network connectivity of mitochondria, as well as facilitating the elimination of damaged mitochondria. Mechanistically, co-immunoprecipitation and mass spectrometry revealed the binding of Atox1 to DJ-1. Knockdown of DJ-1 in HT-22 cells significantly impaired the antioxidant capacity of Atox1. Mutations in the copper-binding motif or sequestration of free copper led to a substantial decrease in the interaction between Atox1 and DJ-1, with overexpression of DJ-1 failing to restore the antioxidant capacity of Atox1 mutants. The findings suggest that DJ-1 mediates the ability of Atox1 to withstand oxidative stress. And targeting Atox1 could be a potential therapeutic approach for addressing post-traumatic neurological dysfunction.
