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.
Keywords: AMPK-PGC1α; Heat shock protein 22; Mitochondria; Subarachnoid hemorrhage.
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