Each year in the US, severe TBI in children results in <7400 deaths and 60 000 hospitalizations. Fifty percent of surviving children with severe TBI have poor neurological outcome at six months. Severe TBI in children is thus a critical problem in desperate need of impactful therapies. Free radicals and oxidative stress have been accepted as universal pathogenic mechanisms of TBI prompting the therapeutic use of antioxidants. Invariably, the clinical trials of non-specific free radical scavengers/antioxidants failed. Unless the true sources and mechanisms of TBI redox imbalance are identified, the use of sacrificial antioxidants and free radical scavengers will fail. Thus, a paradigm-shifting approach is required. During prior funding period, 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. Importantly, our preliminary data show that 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 normal mitochondria, CL and cyt c are physically separated: CL is confined almost exclusively to the inner mitochondrial membrane. Binding of cyt c with CL depends on the collapse of CL asymmetry and translocation of CL to the outer mitochondrial membrane. While the mechanisms of collapse of CL asymmetry are poorly understood, preliminary data show that two candidate proteins - nucleoside diphosphate kinase (NDPK-D) and phospholipid scramblase-3 (PLSCR3) -facilitate CL translocation. Our hypothesis is that collapse of CL asymmetry and formation of cyt c/CL peroxidase complexes trigger - in the presence of H2O2 - CL peroxidation and release of proapoptotic factors from mitochondria in immature brain after TBI. Thus, maintaining CL asymmetry and suppression of peroxidase activity will improve neuronal survival and outcome after TBI. To test our hypothesis and its successful translation, we will employ multi-disciplinary approach combining in vitro (mechanical stretch injury of neurons) and in vivo (controlled cortical impact in PND17 rats) TBI models, biochemical (oxidative lipidomics) and biophysical (new protocols for assessment of asymmetry and externalization of CL in mitochondria) methodology, genetic and pharmacological approaches as well as computational modeling and organic chemical synthesis. These studies will provide important mechanistic information on the role of CL asymmetry and oxidation in neuronal apoptosis after TBI. The ability to selectively modulate CL oxidation, a critical early event in apoptosis, could lead to targeted therapies for TBI and ultimately improve outcome for children after brain injury.
Trauma is the leading cause of death in children. Severe traumatic brain injury (TBI) is the most important component of this mortality and associated morbidity. A specific therapy for TBI does not yet exist and standard treatment remains supportive in nature. This project will identify role of oxidized phospholipids in neuronal death after pediatric TBI using state of the art oxidative lipidomics approach. We will test novel therapeutic compounds in experiments to prevent neuronal death, improve outcome after pediatric TBI. The ability to selectively modulate this pathway could lead to targeted therapies for TBI and ultimately improve outcome for children.
|Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130|
|Anthonymuthu, Tamil S; Kenny, Elizabeth M; Amoscato, Andrew A et al. (2017) Global assessment of oxidized free fatty acids in brain reveals an enzymatic predominance to oxidative signaling after trauma. Biochim Biophys Acta 1863:2601-2613|
|Kagan, Valerian E; Bay?r, Hülya; Tyurina, Yulia Y et al. (2017) Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Biochem Biophys Res Commun 482:482-490|
|Simon, Dennis W; McGeachy, Mandy J; Bay?r, Hülya et al. (2017) The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13:171-191|
|Maguire, John J; Tyurina, Yulia Y; Mohammadyani, Dariush et al. (2017) Known unknowns of cardiolipin signaling: The best is yet to come. Biochim Biophys Acta 1862:8-24|
|Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng et al. (2017) Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. ACS Chem Biol 12:265-281|
|Kagan, Valerian E; Mao, Gaowei; Qu, Feng et al. (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13:81-90|
|Wenzel, Sally E; Tyurina, Yulia Y; Zhao, Jinming et al. (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171:628-641.e26|
|Anthonymuthu, Tamil S; Kim-Campbell, Nahmah; Bay?r, Hülya (2017) Oxidative lipidomics: applications in critical care. Curr Opin Crit Care 23:251-256|
|Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285|
Showing the most recent 10 out of 56 publications