Voltage-dependant anion channels: Novel insights into isoform function through genetic models

Raghavan, Adithya; Sheiko, Tatiana; Graham, Brett H.; Craigen, William J.

doi:10.1016/j.bbamem.2011.10.019

Cited by 79 publications

(84 citation statements)

References 87 publications

(111 reference statements)

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“…Such divergent phenotypes have often been ascribed to background genetic differences between strains of mice (25). For example, deletion of Vdac1 is lethal on the C56Bl6 strain background but viable with a minor metabolic phenotype on other backgrounds (26). In addition to the possibility that strain differences may play a role in these phenotypic differences, ectopic activity of Amhr2-cre deletion has been documented, further supporting our observations.…”

Section: Discussionsupporting

confidence: 75%

Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation

Fan

Campioli

Midzak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

112

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Translocator protein (TSPO) is a key member of the mitochondrial cholesterol transport complex in steroidogenic tissues. To assess the function of TSPO, we generated two lines of Cre-mediated Tspo conditional knockout (cKO) mice. First, gonadal somatic celltargeting Amhr2-Cre mice were crossed with Tspo-floxed mice to obtain F1 Tspo Amhr2 cKO mice (Tspo fl/fl ;Amhr2-Cre /+). The unexpected Mendelian ratio of 4.4% cKO mice was confirmed by genotyping of 12.5-day-postcoitum (dpc) embryos. As Amhr2-Cre is expressed in gonads at 12.5 dpc, these findings suggest preimplantation selection of embryos. Analysis of expression databases revealed elevated levels of Amhr2 in two-and eight-cell zygotes, suggesting ectopic Tspo silencing before the morula stage and demonstrating elevated embryonic lethality and involvement of TSPO in embryonic development. To circumvent this issue, steroidogenic cell-targeting Nr5a1-Cre mice were crossed with Tspofloxed mice. The resulting Tspo fl/fl ;Nr5a1-Cre /+ mice were born at a normal Mendelian ratio. Nr5a1-driven Tspo cKO mice exhibited highly reduced Tspo levels in adrenal cortex and gonads. Treatment of mice with human chorionic gonadotropin (hCG) resulted in increased circulating testosterone levels despite extensive lipid droplet depletion. In contrast, Nr5a1-driven Tspo cKO mice lost their ability to form corticosterone in response to adrenocorticotropic hormone (ACTH). Important for ACTH-dependent steroidogenesis, Mc2r, Stard1, and Cypa11a1 levels were unaffected, whereas Scarb1 levels were increased and accumulation of lipid droplets was observed, indicative of a blockade of cholesterol utilization for steroidogenesis. TSPO expression in the adrenal medulla and increased epinephrine production were also observed. In conclusion, TSPO was found necessary for preimplantation embryo development and ACTH-stimulated steroid biosynthesis.translocator protein | anti-Mullerian hormone receptor type II | nuclear receptor subfamily 5 group A member 1 | knockout mice | steroidogenesis T he 18-kDa translocator protein (TSPO) is an outer mitochondrial membrane (OMM) protein, originally named the peripheral benzodiazepine receptor (PBR) due to its discovery as a high-affinity binding site for the benzodiazepine diazepam outside of the central nervous system (1). Pharmacological, biochemical, and structural research has revealed TSPO's ability to bind numerous classes of drugs (1-4). Additional investigations also demonstrated that TSPO is a high-affinity cholesterol-binding protein. Cholesterol binding is localized to the C-terminal portion of its fifth transmembrane helix at a conserved cholesterol recognition/association amino acid consensus motif (1, 5). This finding was further supported by recent structural data (6). A search for additional physiological ligands of TSPO revealed that both the tetrapyrole protoporphyrin IX, a heme precursor, and the polypeptide endozepine, a GABA A modulator, bind TSPO, suggesting a role for TSPO in numerous physiological processes (1, 2, 5). Interestingly...

show abstract

Section: Discussionsupporting

confidence: 75%

Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation

Fan

Campioli

Midzak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

112

View full text Add to dashboard Cite

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“…-/-mice obtained from a mixed genetic background (C57BL6/129SvEv) were born at a lower than expected mendelian ratio whilst VDAC1 -/-mice, bred onto the C57B16 background, showed near complete lethality (134).…”

Section: Tspo and Its Molecular Partnership With Vdac1mentioning

confidence: 99%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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“…126 These results failed to support a role for VDAC in the PTP. 120,121 However, small interfering RNAs never lead to a complete deficiency, and even a low level of residual VDAC2 could be sufficient to allow normal PTP opening.…”

Section: Genetic Studies Failed To Confirm Ptp Former Candidates Butmentioning

confidence: 99%

Physiological Roles of the Permeability Transition Pore

Brenner

Moulin

2012

Circulation Research

162

136

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Voltage-dependant anion channels: Novel insights into isoform function through genetic models

Cited by 79 publications

References 87 publications

Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation

Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Physiological Roles of the Permeability Transition Pore

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