scholarly journals The mitochondrial DNA genetic bottleneck: inheritance and beyond

2018 ◽  
Vol 62 (3) ◽  
pp. 225-234 ◽  
Author(s):  
Haixin Zhang ◽  
Stephen P. Burr ◽  
Patrick F. Chinnery
Keyword(s):  
Molecular Mechanisms ◽  
Cell Types ◽  
Genetic Bottleneck ◽  
Comprehensive Understanding ◽  
Mtdna Mutations ◽  
Rapid Changes ◽  
Selection For ◽  
Different Levels ◽  
Different Tissues

mtDNA is a multicopy genome. When mutations exist, they can affect a varying proportion of the mtDNA present within every cell (heteroplasmy). Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency seen during transmission from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be revealed. Several questions remain, including the role of selection for and against specific alleles, whether all bottlenecks are the same, and precisely how the bottleneck is controlled during development. Although originally thought to be limited to the germline, there is evidence that bottlenecks exist in other cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. Moreover, tissue-specific bottlenecks may occur throughout life in response to environmental influences, adding further complexity to the situation. Here we review key recent findings, and suggest ways forward that will hopefully advance our understanding of the role of mtDNA in human disease.

scholarly journals Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing

2020 ◽  
Author(s):  
Kashyap Chhatbar ◽  
Justyna Cholewa-Waclaw ◽  
Ruth Shah ◽  
Adrian Bird ◽  
Guido Sanguinetti
Keyword(s):  
Alternative Splicing ◽  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Data Sets ◽  
Learning Approaches ◽  
Global Regulator ◽  
Major Function ◽  
Quantitative Analyses ◽  
Different Levels

AbstractMeCP2 is an abundant protein in mature nerve cells, where it binds to DNA sequences containing methylated cytosine. Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome (RTT), provoking intensive study of the underlying molecular mechanisms. Multiple functions have been proposed, one of which involves a regulatory role in splicing. Here we leverage the recent availability of high-quality transcriptomic data sets to probe quantitatively the potential influence of MeCP2 on alternative splicing. Using a variety of machine learning approaches that can capture both linear and non-linear associations, we show that widely different levels of MeCP2 have a minimal effect on alternative splicing in three different systems. Alternative splicing was also apparently indifferent to developmental changes in DNA methylation levels. Our results suggest that regulation of splicing is not a major function of MeCP2. They also highlight the importance of multi-variate quantitative analyses in the formulation of biological hypotheses.

scholarly journals RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets

2021 ◽  
Author(s):  
Viorica Liebe Lastun ◽  
Matthew Freeman
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Liver Steatosis ◽  
Physiological Role ◽  
Cell Types ◽  
Rhomboid Protease ◽  
Rapid Changes

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes through the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially the ER tubules, how context dependent changes in ER shape and distribution are regulated and the factors involved are less characterized. Here, we show that RHBDL4, an ER-resident rhomboid protease, modulates the shape and distribution of the ER, especially under conditions that require rapid changes in the ER sheet distribution, including ER stress. RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, and with the cytoskeleton. Mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Our data introduce a new physiological role of RHBDL4 and also imply that this function does not require its enzymatic activity.

scholarly journals The role of the liver in the migration of parasites of global significance

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Gwendoline Deslyper ◽  
Derek G. Doherty ◽  
James C. Carolan ◽  
Celia V. Holland
Keyword(s):  
Life Cycle ◽  
Molecular Mechanisms ◽  
Immune Status ◽  
Host Immunity ◽  
Morbidity And Mortality ◽  
Different Tissues

Abstract Many parasites migrate through different tissues during their life-cycle, possibly with the aim to enhance their fitness. This is true for species of three parasite genera of global importance, Ascaris, Schistosoma and Plasmodium, which cause significant global morbidity and mortality. Interestingly, these parasites all incorporate the liver in their life-cycle. The liver has a special immune status being able to preferentially induce tolerance over immunity. This function may be exploited by parasites to evade host immunity, with Plasmodium spp. in particular using this organ for its multiplication. However, hepatic larval attrition occurs in both ascariasis and schistosomiasis. A better understanding of the molecular mechanisms involved in hepatic infection could be useful in developing novel vaccines and therapies for these parasites.

scholarly journals Regulation of TRH neurons and energy homeostasis-related signals under stress

2015 ◽  
Vol 224 (3) ◽  
pp. R139-R159 ◽  
Author(s):  
Patricia Joseph-Bravo ◽  
Lorraine Jaimes-Hoy ◽  
Jean-Louis Charli
Keyword(s):  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Phenotype ◽  
Energy Demands ◽  
Rapid Responses ◽  
Hpt Axis

Energy homeostasis relies on a concerted response of the nervous and endocrine systems to signals evoked by intake, storage, and expenditure of fuels. Glucocorticoids (GCs) and thyroid hormones are involved in meeting immediate energy demands, thus placing the hypothalamo–pituitary–thyroid (HPT) and hypothalamo–pituitary–adrenal axes at a central interface. This review describes the mode of regulation of hypophysiotropic TRHergic neurons and the evidence supporting the concept that they act as metabolic integrators. Emphasis has been be placed on i) the effects of GCs on the modulation of transcription ofTrhin vivoandin vitro, ii) the physiological and molecular mechanisms by which acute or chronic situations of stress and energy demands affect the activity of TRHergic neurons and the HPT axis, and iii) the less explored role of non-hypophysiotropic hypothalamic TRH neurons. The partial evidence gathered so far is indicative of a contrasting involvement of distinct TRH cell types, manifested through variability in cellular phenotype and physiology, including rapid responses to energy demands for thermogenesis or physical activity and nutritional status that may be modified according to stress history.

scholarly journals The Neurobiology of Selenium: Looking Back and to the Future

2021 ◽  
Vol 15 ◽  
Author(s):  
Ulrich Schweizer ◽  
Simon Bohleber ◽  
Wenchao Zhao ◽  
Noelia Fradejas-Villar
Keyword(s):  
Cell Biology ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Epileptic Seizures ◽  
Cell Types ◽  
Mammalian Brain ◽  
The Individual ◽  
The Brain ◽  
Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

scholarly journals The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

2021 ◽  
Vol 22 (4) ◽  
pp. 2194
Author(s):  
Yi-Zhen Wang ◽  
Ebenezeri Erasto Ngowi ◽  
Di Wang ◽  
Hui-Wen Qi ◽  
Mi-Rong Jing ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Cell Types ◽  
Special Focus ◽  
Protective Effects ◽  
Improve Heart Function ◽  
Different Cell Types

Hydrogen sulfide (H2S) has long been considered as a toxic gas, but as research progressed, the idea has been updated and it has now been shown to have potent protective effects at reasonable concentrations. H2S is an endogenous gas signaling molecule in mammals and is produced by specific enzymes in different cell types. An increasing number of studies indicate that H2S plays an important role in cardiovascular homeostasis, and in most cases, H2S has been reported to be downregulated in cardiovascular diseases (CVDs). Similarly, in preclinical studies, H2S has been shown to prevent CVDs and improve heart function after heart failure. Recently, many H2S donors have been synthesized and tested in cellular and animal models. Moreover, numerous molecular mechanisms have been proposed to demonstrate the effects of these donors. In this review, we will provide an update on the role of H2S in cardiovascular activities and its involvement in pathological states, with a special focus on the roles of exogenous H2S in cardiac protection.

scholarly journals Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments

2021 ◽  
Vol 22 (6) ◽  
pp. 2870
Author(s):  
Tsung-Chieh Lin ◽  
Michael Hsiao
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Biological Effects ◽  
Prognostic Significance ◽  
Cell Types ◽  
Receptor Expression ◽  
Specific Cell ◽  
Signaling Axis

Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.

scholarly journals Expression profiling reveals novel role of Hunchback in retinal glia cell development and blood-brain barrier integrity

2017 ◽  
Author(s):  
Montserrat Torres-Oliva ◽  
Julia Schneider ◽  
Gordon Wiegleb ◽  
Felix Kaufholz ◽  
Nico Posnien
Keyword(s):  
Transcription Factor ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Development ◽  
Brain Barrier ◽  
Gene Clustering ◽  
Glia Cell ◽  
Blood Brain

AbstractThe development of different cell types must be tightly coordinated in different organs. The developing head of Drosophila melanogaster represents an excellent model to study the molecular mechanisms underlying this coordination because the eye-antennal imaginal discs contain the organ anlagen of nearly all adult head structures, such as the compound eyes or the antennae. We studied the genome wide gene expression dynamics during eye-antennal disc development in D. melanogaster to identify new central regulators of the underlying gene regulatory network. Expression based gene clustering and transcription factor motif enrichment analyses revealed a central regulatory role of the transcription factor Hunchback (Hb). We confirmed that hb is expressed in two polyploid retinal subperineurial glia cells (carpet cells). Our functional analysis shows that Hb is necessary for carpet cell development and loss of Hb function results in abnormal glia cell migration and photoreceptor axon guidance patterns. Additionally, we show for the first time that the carpet cells are an integral part of the blood-brain barrier.

scholarly journals Synovial Macrophages in Osteoarthritis: The Key to Understanding Pathogenesis?

2021 ◽  
Vol 12 ◽  
Author(s):  
Amanda Thomson ◽  
Catharien M. U. Hilkens
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Disease Development ◽  
Cell Type ◽  
Major Research ◽  
Genetic Characteristics ◽  
Clinical Challenge ◽  
Great Heterogeneity ◽  
Different Tissues

Effective treatment of osteoarthritis (OA) remains a huge clinical challenge despite major research efforts. Different tissues and cell-types within the joint contribute to disease pathogenesis, and there is great heterogeneity between patients in terms of clinical features, genetic characteristics and responses to treatment. Inflammation and the most abundant immune cell type within the joint, macrophages, have now been recognised as possible players in disease development and progression. Here we discuss recent findings on the involvement of synovial inflammation and particularly the role of synovial macrophages in OA pathogenesis. Understanding macrophage involvement may hold the key for improved OA treatments.

scholarly journals Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels

2010 ◽  
Vol 90 (2) ◽  
pp. 559-605 ◽  
Author(s):  
Péter Enyedi ◽  
Gábor Czirják
Keyword(s):  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Detailed Examination ◽  
Resting Membrane Potential ◽  
Membrane Stretch ◽  
Physiological Processes ◽  
Pore Domain ◽  
K Currents

Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

Sign in / Sign up

Export Citation Format

Share Document