Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress. Issue 3 (30th July 2018)

• Record Type: Journal Article
• Authors: Anderson, Corey J.; Kahl, Anja; Qian, Liping; Stepanova, Anna; Starkov, Anatoly; Manfredi, Giovanni; Iadecola, Costantino; Zhou, Ping
• Is Part Of: Journal of neurochemistry. Volume 146:Issue 3(2018)
• Page Start: 235
• Page End: 250
• Publication Date: 2018-07-30
• Subjects: mitochondria -- oxidative stress -- PC12 cells -- prohibitin -- respiratory chain complexes; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14472
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Prohibitin (PHB) is a ubiquitously expressed and evolutionarily conserved mitochondrial protein with multiple functions. We have recently shown that PHB up‐regulation 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 over‐expression promoted cell survival, whereas PHB down‐regulation diminished cell viability. Functionally, manipulation of PHB levels did not affect basal mitochondrial respiration, but it increased spare respiratory capacity. Moreover, PHB over‐expression preserved mitochondrial respiratory function of cells exposed to oxidative stress. Preserved respiratory capacity in differentiated PHB over‐expressing cells exposed to oxidative stress was associated with an elongated mitochondrial morphology, whereas PHB down‐regulation enhanced fragmentation. Mitochondrial complex I oxidative degradation was attenuated by PHB over‐expression 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 down‐regulation 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 the regulation of cardiolipin content. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see:https://cos.io/our-services/open-science-badges/ Abstract : The mitochondrial protein prohibitin (PHB) confers protection against a variety of cellular insults. In this study we manipulated expression of PHB in cells to demonstrate that PHB level regulates the viability of cells in an oxidative stress paradigm and maintains mitochondrial respiratory capacity, morphology, and respiratory complex stability. We show that PHB directly interacts with and maintains the content of the mitochondrial phospholipid cardiolipin (CL) that is required for respiratory chain complex and supercomplex stability and organelle morphology. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see:https://cos.io/our-services/open-science-badges/