Prohibitin Reduces Mitochondrial Free Radical Production and Protects Brain Cells from Different Injury Modalities

作者：Ping Zhou, Liping Qian, Marilena D’Aurelio, Sunghee Cho, Gang Wang, Giovanni Manfredi, Virginia M. Pickel, Costantino Iadecola · 发表于：Journal of Neuroscience · 年份：2012 · DOI：10.1523/jneurosci.2849-11.2012 · 被引用次数：81 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Neuroscience and Neuropharmacology Research

Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types, but its role in neurons remains unclear. In a proteomic screen of rat brains in which ischemic tolerance was induced by electrical stimulation of the cerebellar fastigial nucleus, we found that prohibitin is upregulated in mitochondria. This observation prompted us to investigate the role of prohibitin in neuronal death and survival. We found that prohibitin is upregulated also in the ischemic tolerance induced by transient ischemia in vivo, or oxygen-glucose deprivation in neuronal cultures. Cell fractionation and electron-microscopic immunolabeling studies demonstrated that prohibitin is localized to neuronal mitochondria. Upregulation of prohibitin in neuronal cultures or hippocampal slices was markedly neuroprotective, whereas prohibitin gene silencing increased neuronal vulnerability, an effect associated with loss of mitochondrial membrane potential and increased mitochondrial production of reactive oxygen species. Prohibitin upregulation was associated with reduced production of reactive oxygen species in mitochondria exposed to the complex I inhibitor rotenone. In addition, prohibitin protected complex I activity from the inhibitory effects of rotenone. These observations, collectively, establish prohibitin as an endogenous neuroprotective protein involved in ischemic tolerance. Prohibitin exerts beneficial effects on neurons by reducing mitocho...