Role of prohibitin in ischemic brain injury
Final Report Abstract
We successfully generated transgenic mice selectively overexpressing PHB postnatally in glutamatergic forebrain neurons. PHB Tg mice develop normally and show no difference in stroke pathophysiology relevant parameters. However, PHB Tg mice are protected from focal cerebral ischemia and this effect is not attributable to differences in intra-ischemic CBF. In fact, the increased neuronal expression of PHB is sufficient to confer a remarkable protective effect after focal cerebral ischemia, which strongly correlates with a substantial improvement in sensory-motor performance. The mechanisms of the protection remain unclear, but they may involve increased mitochondrial integrity and suppression of ROS production. To further elucidate the underlying mechanism of PHB mediated neuroprotection, we are currently collaborating with top experts in the field of mitochondrial biogenesis within the institute. The collaboration will involve additional experiments to examine the mitochondrial bioenergetics (oxygen consumption, citrate synthase activity, Calcium capacity) and enzymatic activities of respiratory chain complexes in PHB Tg compared to those of littermates after MCA occlusion. The findings of this project will advance our understanding of the fundamental processes governing neuronal survival and death through regulation of mitochondrial bioenergetics, and may help identify mitochondrial targeted treatment strategies for stroke and other neurological diseases linked to mitochondrial dysfunction.
Publications
- Prohibitin (PHB) expression improves mitochondrial function under oxidative stress in PC12 cells. SfN Meeting 2013 San Diego, Poster: 443.10
Anderson CJ, Kahl A, Qian L, Manfredi G, Iadecola C and Zhou P
- Neuronal overexpression of the mitochondrial protein prohibitin1 is neuroprotective after focal cerebral ischemia. SfN Meeting 2014 Washington DC. Nanosymposium: 672.10
Kahl A, Anderson CJ, Manfredi G, Iadecola C and Zhou P
- Prohibitin complex degradation and OPA1 processing occur early in neurons during oxygen-glucose deprivation. SfN Meeting 2015 Chicago
Anderson CJ, Kahl A, Qian L, Manfredi G, Iadecola C and Zhou P
- Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress. J. of Neurochemistry, Vol 146 Issue 3, August 2018, Pages 235-250
Anderson CJ, Kahl A, Qian L, Starkov A, Manfredi G, Iadecola C and Zhou P
(See online at https://doi.org/10.1111/jnc.14472)
