Mitochondrial Functions and Estrogen Receptor-dependent Nuclear Translocation of Pleiotropic Human Prohibitin 2

Abstract

Proteins with multiple cellular functions provide biological diversity to eukaryotic cells. In the current studies, we identified the mitochondrial functions of human prohibitin 2 (PHB2), which was initially identified as a repressor of estrogen-dependent transcriptional activity. The mitochondrial complex of PHB2 consists of PHB1, voltage-dependent anion channel 2, adenine nucleotide translocator 2, and the anti-apoptotic Hax-1, which is a novel binding partner for PHB2. RNA interference-mediated knockdown of PHB2 in HeLa cells resulted in caspase-dependent apoptosis through down-regulation of Hax-1 and fragmentation of mitochondria. We also found that, although PHB2 is predominantly expressed in the mitochondria of HeLa cells, it translocates to nucleus in the presence of estrogen receptor ␣ and estradiol. Here, we first demonstrated the roles of mammalian PHB2 in mitochondria and the molecular mechanism of its nuclear targeting and showed that PHB2 is a possible molecule directly coupling nuclear-mitochondrial interaction.

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

“…In HeLa cells, mitochondrial PHB2 translocates to the nucleus in the presence of ERa and E2 (ref. 32). These findings suggest the involvement of mammalian PHB2 protein in the regulation of transcription in the nucleus.…”

“…These data suggest that PHB2 can inhibit mitochondrial fission and apoptosis, and PHB2 may antagonize myocardial injury. Previous reports have shown that loss of prohibitins results in the fragmentation of the mitochondrial network in HeLa cells and MEFs 13,14 . The mitochondrial fragmentation of PHB2-depleted MEFs strikingly resembles the mitochondrial morphology observed after OPA1 downregulation 14,27 .…”

“…Furthermore, in other cell types, PHB2 has also been suggested to be localized in the nucleus and modulate transcriptional activity by interacting with transcription factors, including nuclear receptors, either directly or indirectly 12,[29][30][31][32] . PHB2 has been shown to interact with and inhibit the transcriptional activity of the ER in breast cancer 12 .…”

“…PHB2 is mainly localized in the mitochondrial inner membrane and has an important role in regulating mitochondrial morphology. Recent findings suggest that loss of PHB2 results in accumulation of fragmented mitochondria in MEFs and HeLa cells 13,14 . However, the role of PHB2 in mitochondrial dynamics in the heart remains unknown.…”

Prohibitin-2 Binding Modulates Insulin-like Growth Factor-binding Protein-6 (IGFBP-6)-induced Rhabdomyosarcoma Cell Migration

“…In mitochondria, PHB2 interacts with Mdm12p (20) and sphingosine-1-phosphate (42), thereby regulating mitochondrial functions. In the nucleus, PHB2 physically interacts with the estrogen receptor (43) and brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) (44), resulting in suppression of gene transcription and contributing to tumor growth inhibition (10). In the cytosol, PHB2 but not PHB1 binds Akt2 and reciprocally regulates Akt2 levels and muscle differentiation (12,45).…”