Hülya Bayīr, MD

Professor, Department of Critical Care Medicine and Department of Environmental and Occupational Health
Associate Director, Safar Center for Resuscitation Research and Center for Free Radical and Antioxidant Health
University of Pittsburgh
Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA

image of Dr. Hülya Bayır

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)