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Hülya Bayīr, MDProfessor, Department of Critical Care Medicine and Department of Environmental and Occupational Health |
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Abstract: Traumatic brain injury (TBI) is a worldwide problem with high incidence in children and young adults. Fifty percent of surviving children with severe TBI have poor neurological outcome at six months. TBI sets into motion a cascade of biochemical and cellular events with activation of multiple pathways of neuronal death representing viable therapeutic targets. We discovered that selective peroxidation of a mitochondria-specific phospholipid, cardiolipin (CL), occurs in severe pediatric TBI and represents a required mitochondrial stage of neuronal apoptosis. We further identified cytochrome c (cyt c) as a catalyst of CL peroxidation occurring via the formation of cyt c/CL complexes with peroxidase activity triggered by H2O2. Thus cyt c/CL redox interactions and CL peroxidation represent a missing causal link between known reactive oxygen species production and mitochondrial pro-apoptotic responses. Corroborating with this, a mitochondria-targeted small molecule inhibitor of CL peroxidation suppressed TBI-induced apoptosis in vivo and preserved cognitive function in postnatal day (PND) 17 rats. In conclusion the ability to selectively modulate CL oxidation, a critical early event in the mechanism of apoptosis, could lead to targeted therapies for TBI and ultimately improve outcome for children after brain injury. Support: NIH (NS061817, NS076511, NS084604, AI068021) |