title: Prohibitin reduces mitochondrial free radical production and protects brain cells from different injury modalities.
abstract: 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 mitochondrial free radical production. The data with complex I activity suggest that prohibitin may stabilize the function of complex I. The protective effect of prohibitin has potential translational relevance in diseases of the nervous system associated with mitochondrial dysfunction and oxidative stress.
authors.affiliation: Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10065, USA. piz2001@med.cornell.edu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Liping
authors.initials: L
authors.lastname: Qian
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Aurelio
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Virginia
authors.initials: V
authors.lastname: Pickel
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005609:Free Radicals / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D061251:Primary Cell Culture; D000091402:Prohibitins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D005609:Free Radicals; D000091402:Prohibitins; D012097:Repressor Proteins