scholarly journals The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5209
Author(s):  
Stine F. Pedersen ◽  
Mette Flinck ◽  
Luis A. Pardo
Keyword(s):  
Ion Transport ◽  
Cell Fate ◽  
Mitochondrial Function ◽  
Ion Homeostasis ◽  
Reciprocal Relationship ◽  
Cancer Development ◽  
Cellular Functions ◽  
Atp Production ◽  
Cell Fate Decisions

Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis.

scholarly journals Functional Aspects of Seminal Plasma in Bird Reproduction

2020 ◽  
Vol 21 (16) ◽  
pp. 5664
Author(s):  
Julian Santiago-Moreno ◽  
Elisabeth Blesbois
Keyword(s):  
Seminal Plasma ◽  
Ion Homeostasis ◽  
Sperm Concentration ◽  
Cellular Functions ◽  
Functional Aspects ◽  
Reproductive Techniques ◽  
Sperm Survival ◽  
Protein Components ◽  
And Function

This review provides an updated overview of the seminal plasma composition, and the role of metabolic and protein components on the sperm function of avian species. In addition, the implication of seminal plasma on assisted reproductive techniques of birds was discussed. The semen of birds usually has exceptionally high sperm concentration with relatively little seminal plasma, but this contributes to very fast changes in sperm metabolism and function. The biochemical characteristics and physiological roles of the various seminal plasma components in birds (carbohydrates, lipids, amino acids, hormones, and proteins) are poorly understood. Seminal plasma content of proteins has an action on most cellular functions: metabolism, immunity, oxido-reduction regulation, proteolysis, apoptosis, ion homeostasis, and antimicrobial defenses. The variable amount of many proteins is related to a different fertility capacity of poultry sperm. The role of seminal plasma on semen conservation (chilling and freezing) remains largely a matter of speculation, as both inhibitory and stimulating effects have been found. Whereas the presence of seminal plasma did not seem to affect the sperm survival after freezing–thawing, DNA fragmentation is lower in the absence of seminal plasma. The molecular basis of the influence of seminal plasma on sperm cryo-resistance was also discussed in the present review.

A Dual Proto-Oncogenic and Tumor Suppressive Role of LRF/POKEMON In Hemopoietic Malignancies through Control of Cell Fate Decision

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-14-SCI-14
Author(s):  
Pier Paolo Pandolfi
Keyword(s):  
Cell Fate ◽  
Cellular Differentiation ◽  
Conflicts Of Interest ◽  
Human Cancer ◽  
Cellular Transformation ◽  
Related Factor ◽  
Cancer Genes ◽  
Cell Fate Decisions

Abstract Abstract SCI-14 LRF (Leukemia/lymphoma-related factor, also known as POKEMON) is a member of the POZ and Kruppel (POK) family of transcription factors. LRF has been shown to play an essential role in embryonic development and to act as a master regulator of cellular differentiation in virtually any tissue where it is found expressed, including the hemopoietic compartment. As we will discuss, LRF inactivation in the mouse blocks cellular differentiation in both myeloid/erythroid and lymphoid compartments. On the other hand, LRF has been shown to possess a potent proto-oncogenic activity both in vitro and in vivo. In fact, LRF itself can transform primary cells in combination with known oncogenes and is also essential for cellular transformation of mouse embryonic fibroblasts. In addition, overexpression of LRF in immature B and T progenitor cells in vivo in the mouse lead to lethal precursor T-cell lymphoblastic lymphoma/leukemia. In agreement with this notion, LRF is aberrantly expressed in a variety of human cancers, including diffuse large B cell and follicular lymphomas, but also ovarian and breast cancers. Further, the LRF gene is found amplified in a subset of non-small cell lung cancers (NSCLCs), illustrating a direct role in human cancer. However, we speculated that due to the key role of LRF in cell fate decisions, LRF/POKEMON loss could also contribute to tumorigenesis by blocking cellular differentiation. We will discuss provocative in vivo data in support of the notion that LRF/POKEMON can indeed act as a bona fide tumor suppressor representing a compelling example of two-faced cancer genes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals Dysregulation of redox pathways in liver fibrosis

2016 ◽  
Vol 311 (4) ◽  
pp. G667-G674 ◽  
Author(s):  
Natalie J. Torok
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Fate ◽  
Liver Diseases ◽  
Oxygen Species ◽  
Chronic Liver Diseases ◽  
Cell Fate Decisions ◽  
Novel Treatment ◽  
Antioxidant Mechanisms ◽  
Precise Role

Reactive oxygen species are implicated in physiological signaling and cell fate decisions. In chronic liver diseases persistent and increased production of oxidative radicals drives a fibrogenic response that is a common feature of disease progression. Despite our understanding the biology of the main prooxidant enzymes, their targets, and antioxidant mechanisms in the liver, there is still lack of knowledge concerning their precise role in the pathogenesis of fibrosis. This review will examine the role of physiological redox signaling in the liver, provide an overview on recent advances in prooxidant and antioxidant pathways that are dysregulated during fibrosis, and highlight possible novel treatment targets.

scholarly journals O-GlcNAc Homeostasis Controls Cell Fate Decisions During Hematopoiesis

2018 ◽  
Author(s):  
Zhen Zhang ◽  
Matt P. Parker ◽  
Stefan Graw ◽  
Lesya V. Novikova ◽  
Halyna Fedosyuk ◽  
...  
Keyword(s):  
Cell Fate ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Vital Role ◽  
Leukemia Cells ◽  
Cell Fate Decisions ◽  
Expression Of Genes ◽  
All Trans Retinoic Acid ◽  
Glcnac Transferase

AbstractThe addition of O-GlcNAc (a single β-D-N-acetylglucosamine sugar at serine and threonine residues) by O-GlcNAc transferase (OGT) and removal by O-GlcNAcase (OGA) maintains homeostatic levels of O-GlcNAc. We investigated the role of O-GlcNAc homeostasis in hematopoiesis utilizing G1E-ER4 cells carrying a GATA-1 transcription factor fused to the estrogen receptor (GATA-1ER) that undergo erythropoiesis following the addition of β-estradiol (E2) and myeloid leukemia cells that differentiate into neutrophils in the presence of all-trans retinoic acid. During G1E-ER4 differentiation, a decrease in overall O-GlcNAc levels and an increase in GATA-1 interactions with OGT and OGA were observed. Transcriptome analysis on G1E-ER4 cells differentiated in the presence of Thiamet-G (TMG), an OGA inhibitor, identified expression changes in 433 GATA-1 target genes. Chromatin immunoprecipitation demonstrated that the occupancy of GATA-1, OGT, and OGA atLaptm5gene GATA site was decreased with TMG. Myeloid leukemia cells showed a decline in O-GlcNAc levels during differentiation and TMG reduced the expression of genes involved in differentiation. Sustained treatment with TMG in G1E-ER4 cells prior to differentiation caused a reduction of hemoglobin positive cells during differentiation. Our results show that alterations in O-GlcNAc homeostasis disrupt transcriptional programs causing differentiation errors suggesting a vital role of O-GlcNAcylation in control of cell fate.

scholarly journals Cdk8 Kinase Module: A Mediator of Life and Death Decisions in Times of Stress

2021 ◽  
Vol 9 (10) ◽  
pp. 2152
Author(s):  
Brittany Friedson ◽  
Katrina F. Cooper
Keyword(s):  
Cell Death ◽  
Rna Polymerase Ii ◽  
Cell Fate ◽  
Ubiquitin Proteasome System ◽  
Mitochondrial Morphology ◽  
Atp Production ◽  
Cell Fate Decisions ◽  
Regulated Cell Death ◽  
Cyclin C ◽  
Convergence Point

The Cdk8 kinase module (CKM) of the multi-subunit mediator complex plays an essential role in cell fate decisions in response to different environmental cues. In the budding yeast S. cerevisiae, the CKM consists of four conserved subunits (cyclin C and its cognate cyclin-dependent kinase Cdk8, Med13, and Med12) and predominantly negatively regulates a subset of stress responsive genes (SRG’s). Derepression of these SRG’s is accomplished by disassociating the CKM from the mediator, thus allowing RNA polymerase II-directed transcription. In response to cell death stimuli, cyclin C translocates to the mitochondria where it induces mitochondrial hyper-fission and promotes regulated cell death (RCD). The nuclear release of cyclin C requires Med13 destruction by the ubiquitin-proteasome system (UPS). In contrast, to protect the cell from RCD following SRG induction induced by nutrient deprivation, cyclin C is rapidly destroyed by the UPS before it reaches the cytoplasm. This enables a survival response by two mechanisms: increased ATP production by retaining reticular mitochondrial morphology and relieving CKM-mediated repression on autophagy genes. Intriguingly, nitrogen starvation also stimulates Med13 destruction but through a different mechanism. Rather than destruction via the UPS, Med13 proteolysis occurs in the vacuole (yeast lysosome) via a newly identified Snx4-assisted autophagy pathway. Taken together, these findings reveal that the CKM regulates cell fate decisions by both transcriptional and non-transcriptional mechanisms, placing it at a convergence point between cell death and cell survival pathways.

scholarly journals Podocyte bioenergetics in the development of diabetic nephropathy: the role of mitochondria

Endocrinology ◽  
2021 ◽  
Author(s):  
Irena Audzeyenka ◽  
Agnieszka Bierżyńska ◽  
Abigail C Lay
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Signalling Pathways ◽  
Cell Type ◽  
Cellular Functions ◽  
Podocyte Injury ◽  
Underlying Pathogenesis ◽  
Novel Therapeutic

Abstract Diabetic Nephropathy (DN) is the leading cause of kidney failure, with an increasing incidence worldwide. Mitochondrial dysfunction is known to occur in DN and has been implicated in the underlying pathogenesis of disease. These complex organelles have an array of important cellular functions and involvement in signalling pathways; and understanding the intricacies of these responses in health, as well as how they are damaged in disease, is likely to highlight novel therapeutic avenues. A key cell type damaged early in DN is the podocyte and increasing studies have focused on investigating the role of mitochondria in podocyte injury. This review will summarise what is known about podocyte mitochondrial dynamics in DN, with a particular focus on bioenergetic pathways, highlighting key studies in this field and potential opportunities to target, enhance or protect podocyte mitochondrial function in the treatment of DN.

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