Prohibitin (PHB) is a mitochondrial inner membrane protein that may preserve cellular integrity by stabilizing the function of complex I, the electrons entry point into the respiratory chain, and reducing production of mitochondrial reactive oxygen species. In a proteomic study seeking to identify potential neuroprotective proteins expressed in murine models of ischemic tolerance, we found that PHB expression is increased in neuronal mitochondria. These observations raise the possibility that PHB upregulation in preconditioning models promotes neuronal survival, while its downregulation in ischemia facilitates neuronal death. Thus, the long-term objectives of this application are to elucidate the roles of PHB in the brain damage produced by cerebral ischemia and to assess its neuroprotective potential. In particular, we will test the central hypothesis that PHB, by influencing the mitochondrial resistance to injury, is a key determinant of neuronal fate in the ischemic brain. The proposed experiments will use in vitro (oxygen-glucose deprivation), and in vivo (transient forebrain ischemia) models of cerebral ischemic injury. Viral gene transfer and small interfering RNA (siRNA) will be used to increase or decrease PHB expression in neuronal cultures or in the mouse hippocampus. Mitochondrial function will be assessed in neuronal cultures or in isolated mitochondria to explore the mechanisms of the effect of PHB. The following hypotheses will be tested: (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 neuronal cultures is neuroprotective, while its downregulation increases vulnerability to injury;(c) Expression of PHB in the mouse hippocampus protects vulnerable neurons from the damage produced by transient forebrain ischemia;(d) The mechanisms of the neuroprotective effect of PHB involve complex I stabilization and reduced production of mitochondrial reactive oxygen species.

Public Health Relevance

The proposed studies will investigate a novel aspect of the pathobiology of PHB, related to its role in the death and survival of ischemic neurons. The findings will advance our understanding of the fundamental processes regulating ischemic neuronal death, and have the potential of identifying new treatment strategies for ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067078-04
Application #
8303293
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$362,294
Indirect Cost
$147,919
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Kurinami, Hitomi; Shimamura, Munehisa; Ma, Tao et al. (2014) Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction. Stroke 45:1131-8
Woo, Moon-Sook; Wang, Xia; Faustino, Joel V et al. (2012) Genetic deletion of CD36 enhances injury after acute neonatal stroke. Ann Neurol 72:961-70
Zhou, Ping; Qian, Liping; D'Aurelio, Marilena et al. (2012) Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities. J Neurosci 32:583-92
Zhou, Ping; Qian, Liping; Gallo, Eduardo F et al. (2011) The scavenger receptor CD36 contributes to the neurotoxicity of bone marrow-derived monocytes through peroxynitrite production. Neurobiol Dis 42:292-9