Regulation of the Mitochondrial Permeability Transition Pore by the Outer Membrane Does Not Involve the Peripheral Benzodiazepine Receptor (Translocator Protein of 18 kDa (TSPO))

Šileikytė, Justina; Blachly-Dyson, Elizabeth; Sewell, Randall; Carpi, Andrea; Menabò, Roberta; Lisa, Fabio Di; Ricchelli, Fernanda; Bernardi, Paolo; Forte, Michael

doi:10.1074/jbc.m114.549634

Cited by 165 publications

(144 citation statements)

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“…A second isoform, TSPO2, is cell specific and functions in erythroid development (Fan et al, 2009). One of the main functions attributed to mammalian TSPOs is their possible involvement in steroid metabolism and mitochondrial physiology (reviewed in Rupprecht et al, 2010), although recent evidence has challenged these acceptations, showing, for example, that mice TSPO1 is not essential and plays no role in steroidogenesis (Morohaku et al, 2014;Sileikyte et al, 2014;Stocco, 2014). It is well documented that TSPOs can form functional homo-oligomers and heterooligomers with soluble and membrane-bound partners (reviewed in Papadopoulos et al, 2006).…”

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confidence: 99%

The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

et al. 2014

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The Arabidopsis thaliana multi-stress regulator TSPO is transiently induced by abiotic stresses. The final destination of this polytopic membrane protein is the Golgi apparatus, where its accumulation is strictly regulated, and TSPO is downregulated through a selective autophagic pathway. TSPO-related proteins regulate the physiology of the cell by generating functional protein complexes. A split-ubiquitin screen for potential TSPO interacting partners uncovered a plasma membrane aquaporin, PIP2;7. Pull-down assays and fluorescence imaging approaches revealed that TSPO physically interacts with PIP2;7 at the endoplasmic reticulum and Golgi membranes in planta. Intriguingly, constitutive expression of fluorescently tagged PIP2;7 in TSPO-overexpressing transgenic lines resulted in patchy distribution of the fluorescence, reminiscent of the pattern of constitutively expressed yellow fluorescent protein-TSPO in Arabidopsis. Mutational stabilization of TSPO or pharmacological inhibition of the autophagic pathway affected concomitantly the detected levels of PIP2;7, suggesting that the complex containing both proteins is degraded through the autophagic pathway. Coexpression of TSPO and PIP2;7 resulted in decreased levels of PIP2;7 in the plasma membrane and abolished the membrane water permeability mediated by transgenic PIP2;7. Taken together, these data support a physiological role for TSPO in regulating the cell-surface expression of PIP2;7 during abiotic stress conditions through protein-protein interaction and demonstrate an aquaporin regulatory mechanism involving TSPO. INTRODUCTIONEnvironmental stresses such as drought, salinity, or cold are common limiting factors for plant growth and development. These stresses impose osmotic and oxidative stresses at the cellular level, and a critical function of the phytohormone abscisic acid (ABA) is to mediate the plant response to these insults during vegetative growth (Finkelstein et al., 2002;Nambara and Marion-Poll, 2005;Yamaguchi-Shinozaki and Shinozaki, 2006). The increase in active ABA levels in plant cells during water-related stress regulates the expression of ABA-responsive genes by interacting with cytosolic and/or organelle-bound receptors and downstream effectors modulating the activity of defined transcriptional regulators (Fujii and Zhu, 2009;Ma et al., 2009;Park et al., 2009;Wu et al., 2009;Shang et al., 2010). It is thought that up to 10% of the Arabidopsis thaliana transcriptome is responsive to ABA signaling . Extensive studies of stress and ABA-induced gene expression during vegetative growth revealed two waves of response: an early transient response peaking at ;3 h and a late sustained response from 10 h onward (reviewed in Finkelstein, 2013). Characteristically, the so-called "early" genes encode regulatory proteins, such as transcription factors, protein kinases, and phosphatases, and a set of proteins of unknown function Fujita et al., 2006). The "late" genes are presumed to contribute to plant adaptation to the stress and encode proteins such as ...

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The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

et al. 2014

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“…Loss of TSPO had different effects in oxygen consumption rate in different cell types. Decreased oxygen consumption was observed in TSPO-deficient microglia and fibroblasts , but no effects were observed in hepatocytes and Leydig cells (Sileikyte et al 2014. These inconsistent effects are probably attributed to the diversity of mitochondrial types and energetic status of cells.…”

Section: Tspo As An Enzyme For Protoporphyrin IX Degradationmentioning

confidence: 90%

“…The TSPO-NOX2 association (Guilarte et al 2016), remains a hypothesis. The finding that cardiac-specific Tspo cΔ/Δ mice did not show any difference in the extent of ischemia reperfusion injury (Sileikyte et al 2014), a pathology that is partly directed by myocardial NOX2 (Braunersreuther et al 2013), seems to suggest that TSPO and NOX2 may not be a primary mechanism. Perhaps via an interaction of multiple pathways, it is not too surprising that pharmacological evidence has linked TSPO to a variety of mechanisms related to cardioprotection after ischemia reperfusion injury: preventing mitochondrial permeability (Obame et al 2007), increasing activities of mitochondrial oxidative enzymes (Xiao et al 2010) or by reducing mitochondrial cholesterol transport (Paradis et al 2013).…”

Section: :1mentioning

confidence: 90%

“…Effects observed using TSPO-binding drugs (Kinnally et al 1993) and copurification of TSPO with other proteins thought to be involved in MPT (McEnery et al 1992), initially linked TSPO to this process. However, through development of conditional Tspo cΔ/Δ genetic models, it was recently demonstrated that TSPO plays no role in the regulation or structure of the MPT pore (Sileikyte et al 2014). This was another surprising discovery because distinct from steroid synthesis, the validity of a potential alternate mechanism that linked TSPO and TSPO-binding drug action to a number of different neuropathologies was challenged.…”

Section: Tspo Is Not Part Of the Mitochondrial Permeability Transitiomentioning

confidence: 99%

“…In isolated primary microglia from Tspo fl/fl and Tspo −/− mice, measurement of oxygen consumption rate (OCR) indicated that basal OCR was significantly lower in Tspo −/− microglia . In an independent study, OCR compared between Tspo-deficient mitochondria isolated from liver-specific Tspo cΔ/Δ mice and control Tspo fl/fl mice showed no differences in OCR (Sileikyte et al 2014). Although this contrast has been a topic of speculation with respect to the need for an intact cellular environment, and changes to metabolic demand in cells (reviewed in Gut 2015), it subsequently became clear that there was also no correlation between TSPO expression levels and OCR deficits observed in different cell types.…”

Section: Tspo As a Regulator Of Oxygen Consumptionmentioning

confidence: 99%

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Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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F‐ATP synthase and the permeability transition pore: fewer doubts, more certainties

et al. 2019

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Whether the mitochondrial permeability transition pore (PTP), also called mitochondrial megachannel (MMC), originates from the F‐ATP synthase is a matter of controversy. This hypothesis is supported both by site‐directed mutagenesis of specific residues of F‐ATP synthase affecting regulation of the PTP/MMC and by deletion of specific subunits causing dramatic changes in channel conductance. In contrast, human cells lacking an assembled F‐ATP synthase apparently display persistence of the PTP. We discuss recent data that shed new light on this controversy, supporting the conclusion that the PTP/MMC originates from a Ca2+‐dependent conformational change in F‐ATP synthase allowing its reversible transformation into a high‐conductance channel.

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Regulation of the Mitochondrial Permeability Transition Pore by the Outer Membrane Does Not Involve the Peripheral Benzodiazepine Receptor (Translocator Protein of 18 kDa (TSPO))

Cited by 165 publications

References 81 publications

The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

The Arabidopsis Abiotic Stress-Induced TSPO-Related Protein Reduces Cell-Surface Expression of the Aquaporin PIP2;7 through Protein-Protein Interactions and Autophagic Degradation

Current status and future perspectives: TSPO in steroid neuroendocrinology

F‐ATP synthase and the permeability transition pore: fewer doubts, more certainties

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