Mitochondrial–Nuclear Communication by Prohibitin Shuttling under Oxidative Stress

Abstract

Mitochondrial-nuclear communication is critical to maintain mitochondrial activity under stress conditions. Adaptation of the mitochondria-nucleus network to changes in the intracellular oxidation and reduction milieu is critical for the survival of retinal and retinal pigment epithelial (RPE) cells, in relation to their high oxygen demand and rapid metabolism. However, the generation and transmittal of mitochondrial signal to the nucleus remains elusive. Previously, our in vivo study revealed that prohibitin is up-regulated in the retina but is down-regulated in RPE in the aging and diabetic model. In this study, the functional role of prohibitin in the retina and the RPE was studied using biochemical methods, including lipid binding assay, 2D gel electrophoresis, immunocytochemistry, Western blot, and knockdown approach. Protein depletion by siRNA characterized prohibitin as an anti-apoptotic molecule in mitochondria, while lipid binding assay demonstrated subcellular communications between mitochondria and the nucleus under oxidative stress. The changes of the expressions and localization of mitochondrial prohibitin triggered by reactive oxygen species are crucial for mitochondrial integrity. We propose that prohibitin shuttles between mitochondria and the nucleus as an anti-apoptotic molecule and a transcriptional regulator under stress environment in the retina and RPE.

New Biomarkers in the Retina and RPE Under Oxidative Stress

“…The isolation of phosphoproteome or phosphopeptidome represents a potential challenge. Our data and other evidence suggest that phosphorylations are involved in apoptotic or protecting signaling under oxidative stress [Chung et al, 2009;Zhang et al, 2010;Arnouk et al, 2011;Lee et al, 2011;Sripathi et al, 2011].…”

“…We have focused on understanding the cell death mechanism of the retina and RPE under oxidative stress [Chung et al, 2009;Lee et al, 2010a;Lee et al, 2010b;Zhang et al, 2010;Lee et al, 2011;Arnouk et al, 2011;Sripathi et al, 2011]. Our studies demonstrated that oxidative stress may trigger induction of anti-apoptotic erythropoietin, JAK2, and BCL-xL, as well as pro-apoptotic caspases.…”

Spatial Distribution of Cellular Function: The Partitioning of Proteins between Mitochondria and the Nucleus in MCF7 Breast Cancer Cells

“…92 Prohibitin (PHB) translocates from mitochondria to the nucleus under oxidative stress and seems have a dual function as an antiapoptotic molecule that maintains mitochondrial structure and as a transcriptional activator in the nucleus. 93 Prohibitin may also have roles in metabolic switching between glycolysis and fatty acid oxidation, roles as a nuclear transcriptional regulator in interaction with p53, E2F, and Rbn, and roles in regulation of cell cycle transit (see refs in 93). It is known to locate in the nuclear matrix in osteosarcoma MG-63 cancer cells 94 and in MCF7 cells we observed both PHB and PHB2 in the {m&n} protein set (Supporting Information Table 2).…”

Anticancer Strategy Targeting Mitochondrial Biogenesis in Ovarian Cancer

“…Nuclearmitochondrial communication is necessary for the regulation of MtBIO [24]. Prohibitin (PHB), a conserved protein containing PHB domain, has been shown to regulate MtBIO [29], by regulating nuclear-mitochondrial communications [30]. It has been observed that prohibitin 1 (PHB-1) overexpression is related to chemoresistance in ovarian cancer [28].…”

“…MtBIO is the production of daughter mitochondria usually from previously existed one through a division process of called fission, subsequent growth, and maintenance by fusion and autophagy of mitochondria (mitophagy) [24]. Currently it has been observed that MtBIO is associated with cancer chemoresistance [25,26] through the modulation of associated proteins such as methylation-controlled J-protein (MCJ, also known as DNAJC15) [25,27], prohibitin 1 (PHB-1) [28][29][30], myeloid cell leukemia sequence 1 (MCL-1) [31,32] etc. in ovarian cancer.…”