Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ

M19 Modulates Skeletal Muscle Differentiation and Insulin Secretion in Pancreatic β-Cells through Modulation of Respiratory Chain Activity

Mitochondrial dysfunction due to nuclear or mitochondrial DNA alterations contributes to multiple diseases such as metabolic myopathies, neurodegenerative disorders, diabetes and cancer. Nevertheless, to date, only half of the estimated 1,500 mitochondrial proteins has been identified, and the function of most of these proteins remains to be determined. Here, we characterize the function of M19, a novel mitochondrial nucleoid protein, in muscle and pancreatic β-cells. We have identified a 13-long amino acid sequence located at the N-terminus of M19 that targets the protein to mitochondria. Furthermore, using RNA interference and over-expression strategies, we demonstrate that M19 modulates mitochondrial oxygen consumption and ATP production, and could therefore regulate the respiratory chain activity. In an effort to determine whether M19 could play a role in the regulation of various cell activities, we show that this nucleoid protein, probably through its modulation of mitochondrial ATP production, acts on late muscle differentiation in myogenic C2C12 cells, and plays a permissive role on insulin secretion under basal glucose conditions in INS-1 pancreatic β-cells. Our results are therefore establishing a functional link between a mitochondrial nucleoid protein and the modulation of respiratory chain activities leading to the regulation of major cellular processes such as myogenesis and insulin secretion

Cancer Promoted by the Oncoprotein v-ErbA May Be Due to Subcellular Mislocalization of Nuclear Receptors

The retroviral v-ErbA oncoprotein is a highly mutated variant of the thyroid hormone receptor α (TRα), which is unable to bind T3 and interferes with the action of TRα in mammalian and avian cancer cells. v-ErbA dominant-negative activity is attributed to competition with TRα for T3-responsive DNA elements and/or auxiliary factors involved in the transcriptional regulation of T3-responsive genes. However, competition models do not address the altered subcellular localization of v-ErbA and its possible implications in oncogenesis. Here, we report that v-ErbA dimerizes with TRα and the retinoid X receptor and sequesters a significant fraction of the two nuclear receptors in the cytoplasm. Recruitment of TRα to the cytoplasm by v-ErbA can be partially reversed in the presence of ligand and when chromatin is disrupted by the histone deacetylase inhibitor trichostatin A. These results define a new mode of action of v-ErbA and illustrate the importance of cellular compartmentalization in transcriptional regulation and oncogenesis

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mise en evidence d'anomalies de la fonction thyroiedienne neonatale chez l'agneau hypotrophique : origine et consequences physiologiques

SIGLECNRS T 57533 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Influence d’un régime hypercalorique maternel et post-sevrage sur l’état métabolique de la descendance. Implication de l’activité mitochondriale et de la méthylation de l’ADN

La consommation maternelle d'une alimentation déséquilibrée pendant la gestation induit non seulement obésité et diabète de type 2 chez les mères, mais également des désordres métaboliques de longue durée chez leur descendance. Les mitochondries, une cible importante des nutriments, jouent non seulement un rôle clé dans le métabolisme énergétique, mais interviennent également dans la régulation de la sécrétion d’insuline ou la sensibilité des tissus à cette hormone. De plus, une altération de leur fonctionnalité conduit à des changements dans l'activité ADN méthyltransférase altérant ainsi l'expression de plusieurs gènes. Par ailleurs, des modifications de la méthylation du promoteur de gènes codant des régulateurs importants de l’activité mitochondriale, tels que PGC-1α, sont observées dans les maladies métaboliques. Des interactions importantes semblent donc exister entre l’activité mitochondriale et les processus de méthylation de l’ADN, susceptibles de participer à l’induction ou au développement de troubles métaboliques sur le long terme.Les objectifs de ce projet sont de 1) déterminer s’il existe des altérations de l’activité mitochondriale et du profil global de méthylation de l’ADN chez la descendance de mères nourries avec un régime hypercalorique; 2) répondre à la question actuellement en débat sur l’influence respective de la consommation maternelle et post-sevrage de régimes déséquilibrés sur la sévérité des désordres métaboliques observés à l’âge adulte. L’étude est réalisé chez la descendance mâle de rates Wistar ayant reçu un régime standard (C) ou un régime riche en graisses et en sucrose (HFHS) 2 mois avant la conception et pendant toute la durée de la gestation et de la lactation. Au sevrage, les petits ont été mis soit sous le régime standard soit sous le régime HFHS, générant ainsi 4 lots expérimentaux. Différents paramètres sont étudiés chez la descendance aux stades sevrage, 4, 8 et 12 mois : évolution du statut métabolique, évaluation dans le foie et muscle de la fonction mitochondriale, du stress oxydant, analyse de l’expression de gènes impliqués dans la régulation de la mitochondriogenèse, le métabolisme lipidique et la voie insuline, analyse du methylome