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Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress.

TitleProhibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress.
Publication TypeJournal Article
Year of Publication2018
AuthorsAnderson CJ, Kahl A, Qian L, Stepanova A, Starkov A, Manfredi G, Iadecola C, Zhou P
JournalJ Neurochem
Date Published2018 May 28
ISSN1471-4159
Abstract

Prohibitin (PHB) is a ubiquitously expressed and evolutionarily conserved mitochondrial protein with multiple functions. We have recently shown that PHB upregulation offers robust protection against neuronal injury in models of cerebral ischemia in vitro and in vivo, but the mechanism by which PHB affords neuroprotection remains to be elucidated. Here, we manipulated PHB expression in PC12 neural cells to investigate its impact on mitochondrial function and the mechanisms whereby it protects cells exposed to oxidative stress. PHB overexpression promoted cell survival while PHB downregulation diminished cell viability. Functionally, manipulation of PHB levels did not affect basal mitochondrial respiration, but it increased spare respiratory capacity. Moreover, PHB overexpression preserved mitochondrial respiratory function of cells exposed to oxidative stress. Preserved respiratory capacity in differentiated PHB overexpressing cells exposed to oxidative stress was associated with an elongated mitochondrial morphology, while PHB downregulation enhanced fragmentation. Mitochondrial complex I oxidative degradation was attenuated by PHB overexpression and increased in PHB knockdown cells. Changes in complex I degradation were associated with alterations of respiratory chain supercomplexes. Furthermore, we showed that PHB directly interacts with cardiolipin and that downregulation of PHB results in loss of cardiolipin in mitochondria, which may contribute to destabilizing respiratory chain supercomplexes. Taken together, these data demonstrate that PHB modulates mitochondrial integrity and bioenergetics under oxidative stress, and suggest that the protective effect of PHB is mediated by stabilization of the mitochondrial respiratory machinery and its functional capacity, by regulation of cardiolipin content. This article is protected by copyright. All rights reserved.

DOI10.1111/jnc.14472
Alternate JournalJ. Neurochem.
PubMed ID29808474
Grant ListR01 NS067078 / NS / NINDS NIH HHS / United States