Stimulation of Mitochondrial Activity by p43 Overexpression Induces Human Dermal Fibroblast Transformation

Grandemange, Stéphanie; Seyer, Pascal; Carazo, Ángel; Bécuwe, Philippe; Pessemesse, Laurence; Busson, Muriel; Marsac, Cécile; Roger, Pascal; Casas, François; Cabello, Gérard; Wrutniak‐Cabello, Chantal

doi:10.1158/0008-5472.can-04-3652

Cited by 32 publications

(31 citation statements)

References 49 publications

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“…Interestingly, MAFA could also be an indirect target of p43. Indeed, this hypothesis is supported by our previous data indicating that p43 alters ROS production [24], which are known to regulate MAFA protein stability [25]. Last, the observation that the pancreatic phenotype does not worsen with age in p43−/− mice is in accordance with the fact that TRα is weakly expressed in adult mice.…”

Section: Discussionsupporting

confidence: 76%

Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging

et al. 2013

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Thyroid hormones (TH) play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3) receptor (p43) which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43−/− mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43−/− mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43−/− mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.

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Section: Discussionsupporting

confidence: 76%

Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging

et al. 2013

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“…p43 has been shown to control mitochondrial biogenesis in cultured cells [12], [22] and in skeletal muscle [14], [16]. In order to evaluate the influence of p43 deletion on structure of mitochondria in Sertoli and germ cells we performed electron microscopy.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the alteration of mitochondrial morphology observed in p43−/− Sertoli cells is associated with a deregulation of expression of genes which are involved in mitochondrial function. The p43 receptor is known to act as a T3-dependent transcription factor of the mitochondrial genome, which regulates the synthesis of mitochondrial proteins, oxygen consumption and the activities of the complexes of the respiratory chain [12], [13], [22]. In testis, we have measured the expression level of 84 genes involved in various cellular functions of mitochondria including regulators and mediators of mitochondrial molecular transport, metabolites needed for the electron transport chain and oxidative phosphorylation, intrinsic apoptosis pathway genes activated by intracellular damage signalling.…”

Section: Discussionmentioning

confidence: 99%

Depletion of the p43 Mitochondrial T3 Receptor Increases Sertoli Cell Proliferation in Mice

et al. 2013

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Among T3 receptors, TRα1 is ubiquitous and its deletion or a specific expression of a dominant-negative TRα1 isoform in Sertoli cell leads to an increase in testis weight and sperm production. The identification of a 43-kDa truncated form of the nuclear receptor TRα1 (p43) in the mitochondrial matrix led us to test the hypothesis that this mitochondrial transcription factor could regulate Sertoli cell proliferation. Here we report that p43 depletion in mice increases testis weight and sperm reserve. In addition, we found that p43 deletion increases Sertoli cell proliferation in postnatal testis at 3 days of development. Electron microscopy studies evidence an alteration of mitochondrial morphology observed specifically in Sertoli cells of p43−/− mice. Moreover, gene expression studies indicate that the lack of p43 in testis induced an alteration of the mitochondrial-nuclear cross-talk. In particular, the up-regulation of Cdk4 and c-myc pathway in p43−/− probably explain the extended proliferation recorded in Sertoli cells of these mice. Our finding suggests that T3 limits post-natal Sertoli cell proliferation mainly through its mitochondrial T3 receptor p43.

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“…Although the role of mitochondria was long thought to be restricted to an influence on fuel metabolism, the importance of the activity of these organelles has more recently been extended to the regulation of developmental processes. Indeed, mitochondria play a key role in cell survival as well as in the induction of apoptosis (Kroemer G, 2003), cell differentiation Seyer et al, 2006) and cell transformation (Grandemange et al, 2005). Mitochondria have their own genome (mt-DNA) and specific mechanisms for replication, transcription and protein synthesis.…”

Section: Thyroid Hormone Actions: the Mitochondrial Pathwaymentioning

confidence: 99%

Metabolic Action of Thyroid Hormones: Insights from Functional and Proteomic Studies

Silvestri¹,

Lombardi²,

Lange³

et al. 2008

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3,5,3'-triiodo-L-thyronine (T3) modulates development and growth, and in adult life it exerts a profound effect on basal metabolic rate, increasing respiration rate and simultaneously lowering metabolic efficiency. It mainly acts through the coordinated and synergistic modulation of both nuclear and mitochondrial genome expressions giving rise to a complex network of factors and cellular events not yet completely defined. Thus, understanding the effects of T3 requires investigations at several levels [such as genes and gene transcripts (genome and transcriptome), proteins and metabolites, functions and metabolic assessment (proteome and metabolome)]. As yet, the ultimate effects of T3 on tissue-proteomes remain largely unknown. The proteins are excellent targets in disease diagnostics, prognostics, and therapeutics, and therefore proteomic approaches [such as two-dimensional gel electrophoresis (2D-E), two-dimensional liquid chromatography (2-DL), and mass spectrometry (MS)] represent powerful tools for a) the discovery of novel hormone/drug targets and biomarkers, and b) the study of in vivo and in vitro hormone effects on cellular metabolism and protein expressions. Increasingly proteomic techniques are being adopted, in particular to avoid the limitations inherent in the more classical approaches, to solve analytical problems and obtain a more comprehensive identification and characterization of molecular events associated with patho-physiological conditions.Here, we review the new leads emerging from the application of comparative proteomics to the actions of thyroid hormones, and we overview the technologies that can improve the resolution of proteins differing in hydrophobicity, intracellular location, complex formation, and membrane binding.

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Stimulation of Mitochondrial Activity by p43 Overexpression Induces Human Dermal Fibroblast Transformation

Cited by 32 publications

References 49 publications

Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging

Mice Lacking the p43 Mitochondrial T3 Receptor Become Glucose Intolerant and Insulin Resistant during Aging

Depletion of the p43 Mitochondrial T3 Receptor Increases Sertoli Cell Proliferation in Mice

Metabolic Action of Thyroid Hormones: Insights from Functional and Proteomic Studies

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