Mitochondrial translocator protein (TSPO): From physiology to cardioprotection

Morin, Didier; Musman, Julien; Pons, Sandrine; Berdeaux, Alain; Ghaleh, Bijan

doi:10.1016/j.bcp.2015.12.003

Cited by 62 publications

(42 citation statements)

References 173 publications

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“…The ROI templates were made using 11 C-peripheral benzodiazepine receptor (PBR) images of the normal rat heart. The PBR, also known as translocator protein, is an avid protein that is highly expressed in the myocardium 12,13. We could clearly delineate LV and RV using the PET images of 11 C-PBR, which is an established translocator protein imaging agent.…”

Section: Methodsmentioning

confidence: 99%

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Lee

Kang

et al. 2017

Theranostics

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The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized 68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with 68Ga. The efficacy of 68Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. 68Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). 68Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. 68Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with 68Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.

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Section: Methodsmentioning

confidence: 99%

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Lee

Kang

et al. 2017

Theranostics

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“…Translocator protein is an outer mitochondrial membrane which has long been considered as a component of the mPTP and which regulates mitochondria‐mediated apoptotic cell death (Gatliff & Campanella, 2012; Morin, Musman, Pons, Berdeaux, & Ghaleh, 2016). Translocator protein expression is increased in elderly people and in patients with Alzheimer's disease (Kumar et al., 2012; Yasuno et al., 2008).…”

Section: Evidence For the Involvement Of Mptp Opening In Age‐associatmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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“…In response to a moderate oxidative stimulus, overexpressed TSPO can form a complex with VDAC1 [ 31 ], in order to prevent intra-mitochondrial toxic accumulation of calcium [ 8 , 32 ]. In contrast, under more severe conditions of oxidative stress, TSPO and VDAC1 complex with other proteins involved in the formation of the mitochondrial transition pore, promoting apoptosis [ 33 ]. The detection of unchanged levels of apoptotic pathway markers, in our experiments, can confirm a possible saturation of calcium buffering power mediated by mitochondria, which, on the other hand, can cause an enhancement of calcium levels in the cytosol [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

Gliozzi

Scarano

Musolino

et al. 2020

IJMS

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Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a “frail” myocardial tissue unable to adapt itself to stress.

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Mitochondrial translocator protein (TSPO): From physiology to cardioprotection

Cited by 62 publications

References 173 publications

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Mitochondria and aging: A role for the mitochondrial transition pore?

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

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Mitochondrial translocator protein (TSPO): From physiology to cardioprotection

Cited by 62 publications

References 173 publications

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using 68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using 68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Mitochondria and aging: A role for the mitochondrial transition pore?

Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

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Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography