Bag‐1 mediates glucocorticoid receptor trafficking to mitochondria after corticosterone stimulation: Potential role in regulating affective resilience

Luo, Shaolei; Hou, Yachen; Zhang, Yaping; Lei, Feng Ying; Hunter, Richard G.; Yuan, Peixiong; Jia, Yanjie; Li, Haoran; Wang, Gang; Manji, Husseini K.; McEwen, Bruce S.; Xiao, Chunjie; Bao, Hongkun; Du, Jing

doi:10.1111/jnc.15211

Cited by 17 publications

(16 citation statements)

References 47 publications

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“…The important role of Bag-1 in GR mitochondrial translocation was demonstrated when Bag-1 over-expressing cortical neurons blocked the Cort-induced decrease of mitochondrial GR after long-term treatment with high doses of Cort. Consistent with the in vitro results, chronically Cort-treated Bag-1 over-expressing mice blocked the decrease in mitochondrial GR, reversed the anhedonia-like behavior as well as the depressive-like behavior induced by chronic Cort treatment compared to wild type mice [68]. Taken together, GCs exhibit dose-and time-dependent effects on neuronal mitochondrial function, neuronal viability, GR mitochondrial translocation as well as on the formation of the complexes GR/Bcl-2 and GR/Bag-1 in neurons.…”

Section: Neural Cells and Brain Tissuesupporting

confidence: 86%

“…The role of Bag-1 in GR mitochondrial translocation was further investigated by Luo et al who examined Cort dose and time effects on Bag-1/GR complex formation and GR mitochondrial translocation in cortical neuronal cultures and in animal studies [ 68 ]. Their data revealed that short-term treatment with high doses of Cort significantly enhanced the formation of the Bag-1/GR complex and GR mitochondrial translocation, whereas after long-term and high dose incubation of Cort, the Bag-1/GR colocalization and mitochondrial GR were reduced, implicating that Bag-1 mediates the GR mitochondrial trafficking [ 68 ]. The important role of Bag-1 in GR mitochondrial translocation was demonstrated when Bag-1 over-expressing cortical neurons blocked the Cort-induced decrease of mitochondrial GR after long-term treatment with high doses of Cort.…”

Section: Mitochondrial Glucocorticoid Receptor and Apoptosismentioning

confidence: 99%

“…In most disorders of the nervous system, impaired brain mitochondrial dysfunction and selective death of neuronal subtypes are detected [ 90 ]. Bcl-2 and GR chaperones, including Hsp70/90, Bag-1, and FKBP51 are known to be involved in GR mitochondrial trafficking, and therefore can modulate mitochondrial function and apoptosis-mediated processes [ 27 , 68 , 77 ]. Thus, GR chaperones in brain mitochondria have emerged as crucial therapeutic targets for the treatment of neurodegenerative diseases.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…Thus, GR chaperones in brain mitochondria have emerged as crucial therapeutic targets for the treatment of neurodegenerative diseases. Bag-1, an identified target for the actions of mood stabilizers, seems to have an important role in the development of mood disorders while therapies designed to enhance the function of Bag-1 may modulate the effects of stress hormone [ 68 ]. In addition, the selective inhibition of HDAC6 could be also a therapeutic target against GC-induced apoptosis through blocking the mitochondrial translocation of GR and the subsequent mitochondrial dysfunction and activation of intrinsic apoptosis pathway [ 72 ].…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…( b ) Short-term treatment with high doses of Cort enhances the formation of GR/Bag-1 complex and GR mitochondrial localization while long-term treatment with high doses of Cort reduces the mitochondrial GR and GR/Bag-1 colocalization. Chronically Cort-treated Bag-1 overexpressing mice blocked the decrease in mitochondrial GR, reversed the anhedonia-like behavior as well as the depressive-like behavior induced by chronic Cort treatment compared to wild type mice, suggesting that Bag-1 regulates resilience from depressive-like impairments [ 68 ]. GCs; Glucocorticoids, GR; Glucocorticoid Receptor, GREs; Glucocorticoid Response Elements, Bcl2; B-cell lymphoma-2, Bag-1; Bcl-2-associated athanogene, Cort; Corticosterone.…”

Section: Figurementioning

confidence: 99%

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Mitochondrial Glucocorticoid Receptors and Their Actions

Kokkinopoulou

Moutsatsou

2021

IJMS

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Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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Section: Neural Cells and Brain Tissuesupporting

confidence: 86%

Section: Mitochondrial Glucocorticoid Receptor and Apoptosismentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations

Mitochondrial Glucocorticoid Receptors and Their Actions

Kokkinopoulou

Moutsatsou

2021

IJMS

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Mitochondrial–nuclear communication by FKBP51 shuttling

Zgajnar

Lagadari

Gallo

et al. 2023

J of Cellular Biochemistry

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The HSP90‐binding immunophilin FKBP51 is a soluble protein that shows high homology and structural similarity with FKBP52. Both immunophilins are functionally divergent and often show antagonistic actions. They were first described in steroid receptor complexes, their exchange in the complex being the earliest known event in steroid receptor activation upon ligand binding. In addition to steroid‐related events, several pleiotropic actions of FKBP51 have emerged during the last years, ranging from cell differentiation and apoptosis to metabolic and psychiatric disorders. On the other hand, mitochondria play vital cellular roles in maintaining energy homeostasis, responding to stress conditions, and affecting cell cycle regulation, calcium signaling, redox homeostasis, and so forth. This is achieved by proteins that are encoded in both the nuclear genome and mitochondrial genes. This implies active nuclear‐mitochondrial communication to maintain cell homeostasis. Such communication involves factors that regulate nuclear and mitochondrial gene expression affecting the synthesis and recruitment of mitochondrial and nonmitochondrial proteins, and/or changes in the functional state of the mitochondria itself, which enable mitochondria to recover from stress. FKBP51 has emerged as a serious candidate to participate in these regulatory roles since it has been unexpectedly found in mitochondria showing antiapoptotic effects. Such localization involves the tetratricopeptide repeats domains of the immunophilin and not its intrinsic enzymatic activity of peptidylprolyl‐isomerase. Importantly, FKBP51 abandons the mitochondria and accumulates in the nucleus upon cell differentiation or during the onset of stress. Nuclear FKBP51 enhances the enzymatic activity of telomerase. The mitochondrial‐nuclear trafficking is reversible, and certain situations such as viral infections promote the opposite trafficking, that is, FKBP51 abandons the nucleus and accumulates in mitochondria. In this article, we review the latest findings related to the mitochondrial‐nuclear communication mediated by FKBP51 and speculate about the possible implications of this phenomenon.

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