Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome c oxidase

Traumatic brain injury (TBI) is documented to have detrimental effects on C NS metabolism, including alterations in glucose utilization and the depress ion of mitochondrial oxidative phosphorylation. Studies on mitochondrial me tabolism have also provided evidence for reduced activity of the cytochrome oxidase complex of the electron transport chain (complex IV) after TBI and an immediate (1hr) reduction in mitochondrial state 3 respiratory rate, wh ich can persist for up to 14 days postinjury. Using differential display me thods to screen for differences in gene expression, we have found that cyto chrome c oxidase H (COII), a mitochondrial encoded subunit of complex IV, i s upregulated following TBI. Since COH carries a binding site for cytochrom e c in the respiratory chain, and since it is required for the passage of c hain electrons to molecular oxygen, driving the production of ATP, we hypot hesized that metabolic dysfunction resulting from TBI alters COII gene expr ession directly, perhaps influencing the synaptic plasticity that occurs du ring postinjury recovery processes. To test this hypothesis, we documented COII mRNA expression and complex IV (cytochrome c oxidase) functional activ ity at 7 days postinjury, focusing on the long-term postinjury period most closely associated with synaptic reorganization. Both central fluid percuss ion TBI and combined TBI and bilateral entorhinal cortical lesion were exam ined. At 7 days survival, differential display, RT-PCR, and Northern blot a nalysis of hippocampal RNA from both TBI and combined insult models showed a significant induction of COII mRNA. This long-term elevation in COII gene expression was supported by increases in COII immunobinding. By contrast, cytochrome oxidase histochemical activity within tissue sections from injur ed brains suggested a reduction of complex IV activity within the TBI cases , but not within animals subjected to the combined insult. These difference s in cytochrome c oxidase activity were supported by in vitro assay of comp lex IV using cerebral cortical and hippocampal tissues. Our present results support the hypothesis that COH is selectively vulnerable to TBI and that COII differences may indicate the degree of metabolic dysfunction induced b y different pathologies. Taken together, such data will better define the r ole of metabolic function in long-term recovery after TBI.