Interaction du facteur Tuf avec les sequences : activatrices Amont de type UAS_r_p_g de la levure Saccharomyces cerevisiae

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

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

International audienceMitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises

Tunneling Nanotubes (TNTs): Intratumoral Cell-to-Cell Communication and Mitochondria Trafficking Through Connections by Tunneling Nanotubes—Effects on Cell Metabolism and Response to Therapy

International audience

Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury

International audienceMitochondria are crucial organelles that not only regulate the energy metabolism, but also the survival and fate of eukaryotic cells. Mitochondria were recently discovered to be able to translocate from one cell to the other. This phenomenon was observed in vitro and in vivo, both in physiological and pathophysiological conditions including tissue injury and cancer. Mitochondria trafficking was found to exert prominent biological functions. In particular, several studies pointed out that this process governs some of the therapeutic effects of mesenchymal stem cells (MSCs). In this review, we give an overview of the current knowledge on MSC-dependent intercellular mitochondria trafficking and further discuss the recent findings on the intercellular mitochondria transfer between differentiated and mesenchymal stem cells, their biological significance and the mechanisms underlying this process

Intercellular Communication in the Brain through Tunneling Nanotubes

International audienceIntercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine secretion and specialized structures ensuring physical contact between them. Among these intercellular specialized structures, tunneling nanotubes (TNTs) are now recognized as a means of cell-to-cell communication through the exchange of cellular cargo, controlled by a variety of biological triggers, as described here. Intercellular communication is fundamental to brain function. It allows the dialogue between the many cells, including neurons, astrocytes, oligodendrocytes, glial cells, microglia, necessary for the proper development and function of the brain. We highlight here the role of TNTs in connecting these cells, for the physiological functioning of the brain and in pathologies such as stroke, neurodegenerative diseases, and gliomas. Understanding these processes could pave the way for future therapies

The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance

International audienceIntercellular communications play a major role in tissue homeostasis. In pathologies such as cancer, cellular interactions within the tumor microenvironment (TME) contribute to tumor progression and resistance to therapy. Tunneling nanotubes (TNTs) are newly discovered long-range intercellular connections that allow the exchange between cells of various cargos, ranging from ions to whole organelles such as mitochondria. TNT-transferred mitochondria were shown to change the metabolism and functional properties of recipient cells as reported for both normal and cancer cells. Metabolic plasticity is now considered a hallmark of cancer as it notably plays a pivotal role in drug resistance. The acquisition of cancer drug resistance was also associated to TNT-mediated mitochondria transfer, a finding that relates to the role of mitochondria as a hub for many metabolic pathways. In this review, we first give a brief overview of the various mechanisms of drug resistance and of the cellular communication means at play in the TME, with a special focus on the recently discovered TNTs. We further describe recent studies highlighting the role of the TNT-transferred mitochondria in acquired cancer cell drug resistance. We also present how changes in metabolic pathways, including glycolysis, pentose phosphate and lipid metabolism, are linked to cancer cell resistance to therapy. Finally, we provide examples of novel therapeutic strategies targeting mitochondria and cell metabolism as a way to circumvent cancer cell drug resistance. Mechanisms of drug resistance Resistance to cancer therapy is still a major obstacle for effective and lasting treatment, resulting in relapse, metastasis and reduced overall survival. Many mechanisms have been described that foster this resistance, including both cell autonomous (or intrinsic) and extrinsic processes, the latter greatly resulting from the tumor microenvironment (TME) complexity [1,2]. It is indeed becoming increasingly evident that tumors do not behave as masses of homogeneous malignant cells, but rather as complex, full-fledged 'organs' in dynamic progression through time and space, resulting in enhanced tumor fitness and resistance to therapy [3,4]. Drug resistance intrinsic processes Understanding the drug resistance molecular mechanisms is more crucial than ever in order to achieve effective and long-lasting cancer therapy. The mechanisms of drug resistance include drug transporters, DNA damage repair (DDR) and genomic instability, apoptosis inhibition and metabolic adaptation [5,6]. Unfortunately, these mechanisms often overlap in the context of cancer, adding an extra layer of complexity that often precludes the full deciphering of all resistance causes

Opposite Effects of Transforming Growth Factor-β Activation and Rho-Associated Kinase Inhibition on Human Trophoblast Migration in a Reconstituted Placental-Endometrial Coculture System

International audiencePlacental implantation involves highly regulated trophoblast invasion of the endometrial stroma. TGF is a known regulator of this process. This study examines the effect of TGF on extravillous cytotrophoblastic cell (EVCT) migration in cocultures of first-trimester human chorionic villus explants and primary human endometrial fibroblasts. Migration of EVCTs was followed by phase-contrast time-lapse micros-copy and was shown to highly depend on the endometrial fibroblast matrix. Interstitial EVCT invasion was also analyzed by confocal microscopy of fluorescently prelabeled trophoblasts and endometrial fibroblasts. As expected, addition of TGF led to inhibition of EVCT invasion of the endometrial cell layer. This inhibition was characterized by formation of compact EVCT stacks at migration fronts and displacement of endometrial fibroblasts. We tested the role of the RhoA/Rho-associated kinase (ROCK) pathway, a TGF-dependent pathway known to regulate cell migration. Interestingly, blocking ROCK with the chemical in-hibitor Y27632 had an effect opposite to TGF activation because it promoted superficial EVCT migration on the en-dometrial cell layer. These data suggest a role for ROCK in the TGF-dependent control of trophoblast migration. Furthermore , they indicate that even though ROCK signaling plays a role in human trophoblast cell invasion, EVCT migration can still occur in the absence of ROCK activity. (Endocrinology 149: 4475– 4485, 2008

Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy

International audienceIntercellular communications play a major role in tissue homeostasis and responses to external cues. Novel structures for this communication have recently been described. These tunneling nanotubes (TNTs) consist of thin-extended membrane protrusions that connect cells together. TNTs allow the cell-to-cell transfer of various cellular components, including proteins, RNAs, viruses, and organelles, such as mitochondria. Mesenchymal stem cells (MSCs) are both naturally present and recruited to many different tissues where their interaction with resident cells via secreted factors has been largely documented. Their immunosuppressive and repairing capacities constitute the basis for many current clinical trials. MSCs recruited to the tumor microenvironment also play an important role in tumor progression and resistance to therapy. MSCs are now the focus of intense scrutiny due to their capacity to form TNTs and transfer mitochondria to target cells, either in normal physiological or in pathological conditions, leading to changes in cell energy metabolism and functions, as described in this review

Methods for simultaneous and quantitative isolation of mitochondrial DNA, nuclear DNA and RNA from mammalian cells

International audienceThe aim of this study was to assess two protocols for their capacities to simultaneously isolate RNA, mtDNA and ncDNA from mammalian cells. We compared the Invitrogen TRIzol-based method and Qiagen DNeasy columns, using the HepG2 cell line and human primary glioblastoma stem cells. Both methods allowed the isolation of all three types of nucleic acids and provided similar yields in mtDNA. However, the yield in ncDNA was more than tenfold higher on columns, as observed for both cell types. Conversely, the TRIzol method proved more reproducible and was the method of choice for isolating RNA from glioblastoma cells, as demonstrated for the housekeeping genes RPLP0 and RPS9