Role of prohibitin in ischemic brain injury

• Applicant: Dr. Anja Kahl
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233091909

Prohibitin (PHB) is a highly conserved mitochondrial inner membrane protein that may preserve cellular integrity by stabilizing the function of the respiratory chain complex I, subsequently reducing the production of mitochondrial reactive oxygen species (ROS). In a proteomic study seeking to identify potential neuroprotective proteins, PHB expression was found to be increased in neuronal mitochondria. Furthermore, upregulation of PHB in neuronal cultures or hippocampal slices was markedly neuroprotective in different models of ischemic injury. These observations raise the possibility that PHB upregulation promotes neuronal survival, while its downregulation is associated with increased neuronal vulnerability to ischemic brain injury. Thus, the long-term objectives of this application are to elucidate the role of PHB in ischemic brain damage and to assess its neuroprotective potential. Particularly, testing the central hypothesis, that PHB is a key determinant of neuronal fate by influencing the mitochondrial resistance to ischemic induced brain injury. The proposed experiments will use in vitro (oxygen-glucose deprivation, OGD), and in vivo (transient forebrain ischemia, BCCAO) models of cerebral ischemia. Viral gene transfer will be used to increase PHB expression in mouse hippocampus. Mitochondrial function will be assessed in primary neuronal cultures and isolated mitochondria to explore the mechanisms of PHB action. The following hypotheses will be addressed: (a) Hypoxia-ischemia downregulates PHB, a reduction that decreases endogenous defense mechanisms and may increase the susceptibility of the brain to injury; (b) Expression of PHB in the mouse hippocampus protects vulnerable neurons from the damage produced by transient forebrain ischemia; (c) The mechanisms of the neuroprotective effect of PHB involve complex I stabilization and reduced production of mitochondrial ROS. The findings of the present proposal will provide new insights about the beneficial role of PHB in cerebral ischemia, potentially revealing novel therapeutic strategies and pharmacological targets to counteract the deleterious effect of ischemic stroke.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Costantino Iadecola