TSPO is a REDOX regulator of cell mitophagy

Gatliff, Jemma; Campanella, Michelangelo

doi:10.1042/bst20150037

Cited by 54 publications

(45 citation statements)

References 112 publications

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“…Indeed, several lines of evidence demonstrate an intrinsic role of TSPO in ROS generation, which ultimately impacts cell viability and survival. TSPO can up-regulate the production of ROS in complex with the voltage-dependent anion channel (VDAC1) of the outer mitochondrial membrane, as overexpression of the protein is associated with increased oxidative stress [178] and involvement in apoptotic pathways [179]. Lin et al [180] demonstrated that inactivation of the Tspo homolog in Drosophila decreased caspase 3/7 activity and inhibited apoptosis triggered by 30 Gy gamma radiation and H 2 O 2 exposure.…”

Section: Mitochondrial Translocator Protein 18 Kda (Tspo) In Neuroinfmentioning

confidence: 99%

The impact of high and low dose ionising radiation on the central nervous system

et al. 2016

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Responses of the central nervous system (CNS) to stressors and injuries, such as ionising radiation, are modulated by the concomitant responses of the brains innate immune effector cells, microglia. Exposure to high doses of ionising radiation in brain tissue leads to the expression and release of biochemical mediators of ‘neuroinflammation’, such as pro-inflammatory cytokines and reactive oxygen species (ROS), leading to tissue destruction. Contrastingly, low dose ionising radiation may reduce vulnerability to subsequent exposure of ionising radiation, largely through the stimulation of adaptive responses, such as antioxidant defences. These disparate responses may be reflective of non-linear differential microglial activation at low and high doses, manifesting as an anti-inflammatory or pro-inflammatory functional state. Biomarkers of pathology in the brain, such as the mitochondrial Translocator Protein 18 kDa (TSPO), have facilitated in vivo characterisation of microglial activation and ‘neuroinflammation’ in many pathological states of the CNS, though the exact function of TSPO in these responses remains elusive. Based on the known responsiveness of TSPO expression to a wide range of noxious stimuli, we discuss TSPO as a potential biomarker of radiation-induced effects.

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Section: Mitochondrial Translocator Protein 18 Kda (Tspo) In Neuroinfmentioning

confidence: 99%

The impact of high and low dose ionising radiation on the central nervous system

et al. 2016

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“…[10], [11] These pathways play an essential role in maintaining mitochondrial turnover and quality control. [10], [12] Zhan M et al recently observed decreased tubular cell mitophagy in high-glucose (HG) ambient and the kidneys of STZ-induced diabetic mice, a process that was mediated by myo-inositol oxygenase (MIOX) via PINK/Parkin and was negatively correlated with ROS overproduction, mitochondrial fragmentation and apoptosis. [3] Huang CH et al demonstrated that mitophagy inhibition was associated with tubular damage via the thioredoxin interacting protein (TXNIP)/mTOR/BNIP3 signaling pathway in diabetic mice.…”

Section: Introductionmentioning

confidence: 99%

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

et al. 2017

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Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

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“…The idea that overexpression of TSPO creates an oxidative cellular environment is very important as the expression of the Tspo is driven by downstream effectors of ROS (48). Under oxidative conditions, an increase in TSPO levels may be physiologically important to provide mitochondrial and cellular protection against initial ROS damage; should this be sustained, a positive feedback cycle in which the gene is re-expressed and mitophagy continuously impaired may manifest by leading to cumulative mitochondrial damage, which would impact cell and tissue health over time (53).…”

Section: Steroidogenic Nih-3t3 Cells (42)mentioning

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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TSPO is a REDOX regulator of cell mitophagy

Cited by 54 publications

References 112 publications

The impact of high and low dose ionising radiation on the central nervous system

The impact of high and low dose ionising radiation on the central nervous system

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

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

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