Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner
Shenghao Zhang,
Xun Wu,
Jin Wang,
Yingwu Shi,
Qing Hu,
Wenxing Cui,
Hao Bai,
Jinpeng Zhou,
Yong Du,
Liying Han,
Leiyang Li,
Dayun Feng,
Shunnan Ge,
Yan Qu
Affiliations
Shenghao Zhang
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Xun Wu
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Jin Wang
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Yingwu Shi
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Qing Hu
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Wenxing Cui
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Hao Bai
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Jinpeng Zhou
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Yong Du
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Liying Han
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Leiyang Li
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Dayun Feng
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Shunnan Ge
Corresponding author.; Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Yan Qu
Corresponding author.; Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.
