Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats
Haiyan Fan,
Rui Ding,
Wenchao Liu,
Xin zhang,
Ran Li,
Boyang Wei,
Shixing Su,
Fa Jin,
Chengcong Wei,
Xuying He,
Xifeng Li,
Chuanzhi Duan
Affiliations
Haiyan Fan
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Rui Ding
Department of Cerebrovascular Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China
Wenchao Liu
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Xin zhang
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Ran Li
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Boyang Wei
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Shixing Su
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Fa Jin
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Chengcong Wei
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Xuying He
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
Xifeng Li
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China; Corresponding author.
Chuanzhi Duan
Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China; Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, 510280, Guangdong, China; Corresponding author. Department of Cerebrovascular Surgery, Neurosurgery Center, Zhujiang Hospital, Southern Medical University, No.253. Gongye Middle Avenue, Haizhu District, Guangzhou, 510280, Guangdong, China.
Mitochondrial dysfunction has been widely accepted as a detrimental factor in subarachnoid hemorrhage (SAH)-induced early brain injury (EBI), which is eminently related to poor neurologic function outcome. Previous studies have revealed that enhancement of heat shock protein 22 (hsp22) under conditions of stress is a friendly mediator of mitochondrial homeostasis, oxidative stress and apoptosis, thus accelerating neurological recovery. However, no study has confirmed whether hsp22 attenuates mitochondrial stress and apoptosis in the setting of SAH-induced EBI. Our results indicated that endogenous hsp22, p-AMPK/AMPK, PGC1α, TFAM, Nrf1 and Drp1 were significantly upregulated in cortical neurons in response to SAH, accompanied by neurologic impairment, brain edema, neuronal degeneration, lower level of mtDNA and ATP, mitochondria-cytosol translocation of cytochrome c, oxidative injury and caspase 3-involved mitochondrial apoptosis. However, exogenous hsp22 maintained neurological function, reduced brain edema, improved oxidative stress and mitochondrial apoptosis, these effects were highly dependent on PGC1α-related mitochondrial biogenesis/fission, as evidenced by co-application of PGC1α siRNA. Furthermore, we demonstrated that blockade of AMPK with dorsomorphin also compromised the neuroprotective actions of hsp22, along with the alterations of PGC1α and its associated pathway molecules. These data revealed that hsp22 exerted neuroprotective effects by salvaging mitochondrial function in an AMPK-PGC1α dependent manner, which modulates TFAM/Nrf1-induced mitochondrial biogenesis with positive feedback and DRP1-triggered mitochondrial apoptosis with negative feedback, further reducing oxidative stress and brain injury. Boosting the biogenesis and repressing excessive fission of mitochondria by hsp22 may be an efficient treatment to relieve SAH-elicited EBI.
