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Christine S Gibhardt

Other affiliations: Saarland University
Bio: Christine S Gibhardt is an academic researcher from University of Göttingen. The author has contributed to research in topics: Oxidative stress & Melanoma. The author has an hindex of 6, co-authored 12 publications receiving 179 citations. Previous affiliations of Christine S Gibhardt include Saarland University.

Papers
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Journal ArticleDOI
TL;DR: Current knowledge on the role of the mitochondrial calcium uniporter (MCU) complex in multiple cancer types and models is reviewed and a perspective for future research and clinical considerations is provided.
Abstract: The important role of mitochondria in cancer biology is gaining momentum. With their regulation of cell survival, metabolism, basic cell building blocks, and immunity, among other functions, mitochondria affect not only cancer progression but also the response and resistance to current treatments. Calcium ions are constantly shuttled in and out of mitochondria; thus, playing an important role in the regulation of various cellular processes. The mitochondrial calcium uniporter (MCU) channel and its associated regulators transport calcium across the inner mitochondrial membrane to the mitochondrial matrix. Due to this central role and the capacity to affect cell behavior and fate, the MCU complex is being investigated in different cancers and cancer-related conditions. Here, we review current knowledge on the role of the MCU complex in multiple cancer types and models; we also provide a perspective for future research and clinical considerations.

77 citations

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TL;DR: The results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses and generated a mathematical model that predicted additional features of the Ca2+-redox interplay.
Abstract: In phagocytes, pathogen recognition is followed by Ca 2+ mobilization and NADPH oxidase 2 (NOX2)–mediated “oxidative burst,” which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca 2+ channels control store-operated Ca 2+ entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca 2+ -redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.

54 citations

Journal ArticleDOI
TL;DR: This study unravels a novel redox‐controlled ER–mitochondria–NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.
Abstract: Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.

51 citations

Journal ArticleDOI
TL;DR: A brief guide that will help scientists choose the right combination of Ca(2+) and redox sensors to answer specific scientific questions is provided.

26 citations

Journal ArticleDOI
TL;DR: The analyses show that loss of COA6 causes combined complex I and complex IV deficiency and impacts membrane potential-driven protein transport across the inner membrane, and defines COA 6 as thiol-reductase, which is essential for CuA biogenesis.

25 citations


Cited by
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Book ChapterDOI
01 Jan 2019
TL;DR: The global concept of oxidative stress is defined as an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage as discussed by the authors.
Abstract: The global concept of oxidative stress is defined as “an imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage” (see Sies and Jones11). In accordance with H. Selye's initial concept of stress, the term oxidative stress implies an adaptive oxidative stress response. Physiological (low-level) oxidative stress is used in redox signaling and redox regulation, termed oxidative eustress, whereas supraphysiological oxidative challenge leads to disrupted redox signaling and/or oxidative damage to biomolecules, oxidative distress. Much current research effort addresses the consequences in biology and medicine. Using newly developed methods, detailed information on spatiotemporal redox patterns and their regulation in specific settings is becoming accessible.

516 citations

Journal ArticleDOI
TL;DR: In the past decade, it is has become clear that Membrane Contact Sites (MCSs) have a much broader range of critical roles in cells than was initially thought as mentioned in this paper, and functions for MCSs in intracellular signalling such as autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have been reported.
Abstract: Organelles compartmentalize eukaryotic cells, enhancing their ability to respond to environmental and developmental changes. One way in which organelles communicate and integrate their activities is by forming close contacts, often called 'membrane contact sites' (MCSs). Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of critical roles in cells than was initially thought. Indeed, functions for MCSs in intracellular signalling (particularly calcium signalling, reactive oxygen species signalling and lipid signalling), autophagy, lipid metabolism, membrane dynamics, cellular stress responses and organelle trafficking and biogenesis have now been reported.

320 citations

Journal ArticleDOI
TL;DR: The regulation of Ca2+ channels and transporters by oxidants are described and the potential consequences of the ROS-Ca2+ interplay in tumor cells are discussed.

149 citations

Journal ArticleDOI
TL;DR: Both Cu(I) and Cu(II) binding are critical for normal Sco function, according to a study of soluble domains of human and yeast Sco1 and Sco2.

133 citations

Journal ArticleDOI
TL;DR: A link between oxidative stress and hypertension has been established in multiple animal models of hypertension but remains elusive in humans while initial studies focused on inactivation of nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly.
Abstract: A link between oxidative stress and hypertension has been firmly established in multiple animal models of hypertension but remains elusive in humans While initial studies focused on inactivation of nitric oxide by superoxide, our understanding of relevant reactive oxygen species (superoxide, hydrogen peroxide, and peroxynitrite) and how they modify complex signaling pathways to promote hypertension has expanded significantly In this review, we summarize recent advances in delineating the primary and secondary sources of reactive oxygen species (nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, endoplasmic reticulum, and mitochondria), the posttranslational oxidative modifications they induce on protein targets important for redox signaling, their interplay with endogenous antioxidant systems, and the role of inflammasome activation and endoplasmic reticular stress in the development of hypertension We highlight how oxidative stress in different organ systems contributes to hypertension, describe new animal models that have clarified the importance of specific proteins, and discuss clinical studies that shed light on how these processes and pathways are altered in human hypertension Finally, we focus on the promise of redox proteomics and systems biology to help us fully understand the relationship between ROS and hypertension and their potential for designing and evaluating novel antihypertensive therapies

125 citations