APE1 regulates mitochondrial DNA damage repair after experimental subarachnoid haemorrhage in vivo and in vitro

• DOI: 10.1136/svn-2023-002524
• Publication Date: 2023-08-23T15:21:10Z
• Authors: Kun Dai; Zongqi Wang; Bixi Gao; Longyuan Li; Feng Gu; Xinyu Tao; Wanchun You; Zhong Wang
• Keywords: Male; Neurons; Time Factors; DNA Repair; Behavior, Animal; Subarachnoid Hemorrhage; DNA, Mitochondrial; 3. Good health; Mitochondria; Rats, Sprague-Dawley; Disease Models, Animal; Oxyhemoglobins; DNA-(Apurinic or Apyrimidinic Site) Lyase; Animals; Neurology. Diseases of the nervous system; RC346-429; Energy Metabolism; Cells, Cultured; Original Research; DNA Damage

Background

Subarachnoid haemorrhage (SAH) can result in a highly unfavourable prognosis. In recent years, the study of SAH has focused on early brain injury (EBI), which is a crucial progress that contributes to adverse prognosis. SAH can lead to various complications, including mitochondrial dysfunction and DNA damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein with multifaceted functionality integral to DNA repair and redox signalling. However, the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear.

Methods Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention. Then, the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot, immunofluorescence, quantitative real-time PCR, mitochondrial bioenergetics measurement and neurobehavioural experiments.

Results We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH. Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH. In vitro, after primary neurons exposed to oxyhaemoglobin, APE1 expression significantly decreased along with increased mitochondrial DNA damage, a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction. Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis.

Conclusion In conclusion, APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain. APE1 may potentially play a vital role in the EBI stage after SAH, making it a critical target for treatment.