scholarly journals Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Margaret A M Nelson ◽  
Kelsey L McLaughlin ◽  
James T Hagen ◽  
Hannah S Coalson ◽  
Cameron Schmidt ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Atp Synthesis ◽  
Therapeutic Index ◽  
Cell Types ◽  
Mitochondrial Metabolism ◽  
Metabolic Phenotype ◽  
Hematopoietic Stem ◽  
Cellular Processes ◽  
Underlying Mechanisms ◽  
Primary Output

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes seemingly critical for malignant growth. As such, there is considerable interest in targeting mitochondrial metabolism in cancer. However, notwithstanding the few drugs targeting mutant dehydrogenase activity, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? Such information is particularly critical for the subset of human cancers, including acute myeloid leukemia (AML), in which alterations in mitochondrial metabolism are implicated in various aspects of cancer biology (e.g., clonal expansion and chemoresistance). Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in various hematological cell types, with a specific focus on OXPHOS dynamics in AML. Consistent with prior reports, clonal cell expansion, characteristic of leukemia, was universally associated with a hyper-metabolic phenotype which included increases in basal and maximal glycolytic and respiratory flux. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic limitations in oxidative ATP synthesis (i.e., OXPHOS). Remarkably, by performing experiments across a physiological span of ATP free energy (i.e, ΔGATP), we provide direct evidence that, rather than contributing to cellular ΔGATP, leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of OXPHOS kinetics proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Taken together, these findings argue against ATP being the primary output of mitochondria in leukemia and provide proof-of-principle that restoring, rather than disrupting, OXPHOS and/or cellular ΔGATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

scholarly journals Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia.

2021 ◽  
Author(s):  
Margaret Nelson ◽  
Kelsey McLaughlin ◽  
James Hagen ◽  
Hannah Coalson ◽  
Cameron Schmidt ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Atp Synthesis ◽  
Therapeutic Index ◽  
Cell Types ◽  
Mitochondrial Metabolism ◽  
Metabolic Phenotype ◽  
Hematopoietic Stem ◽  
Cellular Processes ◽  
Underlying Mechanisms ◽  
Primary Output

Abstract Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes seemingly critical for malignant growth. As such, there is considerable interest in targeting mitochondrial metabolism in cancer. However, notwithstanding the few drugs targeting mutant dehydrogenase activity, nearly all hopeful ‘mito-therapeutics’ cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? Such information is particularly critical for the subset of human cancers, including acute myeloid leukemia (AML), in which alterations in mitochondrial metabolism are implicated in various aspects of cancer biology (e.g., clonal expansion and chemoresistance). Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in various hematological cell types, with a specific focus on OXPHOS dynamics in AML. Consistent with prior reports, clonal cell expansion, characteristic of leukemia, was universally associated with a hyper-metabolic phenotype which included increases in basal and maximal glycolytic and respiratory flux. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic limitations in oxidative ATP synthesis (i.e., OXPHOS). Remarkably, by performing experiments across a physiological span of ATP free energy (i.e, ΔGATP), we provide direct evidence that, rather than contributing to cellular ΔGATP, leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of OXPHOS kinetics proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Taken together, these findings argue against ATP being the primary output of mitochondria in leukemia and provide proof-of-principle that restoring, rather than disrupting, OXPHOS and/or cellular ΔGATP in cancer may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.

scholarly journals Oxidative stress and its role in cancer: a molecular perspective

2020 ◽  
Author(s):  
Georgina Crespo ◽  
Luis Alejandro Di Toro ◽  
Valbuena Desiree ◽  
Jose Luis Perez Vicuña ◽  
María Paula Díaz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Cancer Biology ◽  
Therapeutic Potential ◽  
Typical Feature ◽  
Cellular Growth ◽  
System Capacity ◽  
Antioxidant Systems ◽  
Cellular Processes ◽  
Underlying Mechanisms

Cancer development is a product of cellular growth and proliferation caused by DNA mutations, nevertheless, other processes are able to favor tumoral progression, such as the activity of reactive oxygen species (ROS) produced within cells as a result of different metabolic reactions. Oxidative stress is defined as an imbalance between free radicals and highly reactive metabolites synthesis and the antioxidant system capacity to eliminate these molecules. In this sense, the overproduction of free radicals is a typical feature of neoplastic cells that allows the promotion of cellular processes related to survival, proliferation, invasion, and metastasis. Furthermore, underlying mechanisms involved in malignant transformation can modify the antioxidant systems in charge of ROS elimination. However, cancer has the particularity of presenting a dual behavior in which both antioxidant or prooxidant activity within tumoral cells can predominate depending on the stage of the disease. As a consequence, many therapeutic efforts have been directed into the stimulation or inhibition of oxidant and antioxidant components in the tumor microenvironment. The aim of this review is to describe the role of oxidative stress in cancer biology and its therapeutic potential.

scholarly journals Single cell micro-pillar-based characterization of endothelial and fibroblast cell mechanics

2021 ◽  
Author(s):  
Julia Eckert ◽  
Yasmine Abouleila ◽  
Thomas Schmidt ◽  
Alireza Mashaghi
Keyword(s):  
Single Cell ◽  
Force Measurement ◽  
Traction Force ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Fibroblast Cells ◽  
Cellular Processes ◽  
Sense And Respond ◽  
Underlying Mechanisms

Mechanotransduction, the ability of cells to sense and respond to the mechanical cues from their microenvironment, plays an important role in numerous cellular processes, ranging from cell migration to differentiation. Several techniques have been developed to investigate the underlying mechanisms of mechanotransduction, in particular, force measurement-based techniques. However, we still lack basic single cell quantitative comparison on the mechanical properties of commonly used cell types, such as endothelial and fibroblast cells. Such information is critical to provide a precedent for studying complex tissues and organs that consist of various cell types. In this short communication, we report on the mechanical characterization of the commonly used endothelial and fibroblast cells at the single cell level. Using a micropillar-based assay, we measured the traction force profiles of these cells. Our study showcases differences between the two cell types in their traction force distribution and morphology. The results reported can be used as a reference and to lay the groundwork for future analysis of numerous disease models involving these cells.

scholarly journals SUN-743 Understanding the Role of Pancreas and Testis Specific lncRNA86 in Estrogen-Dependent Signaling in Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Enrique Ivan Ramos ◽  
Barbara Yang ◽  
Ramesh Choudhari ◽  
Laura Sanchez-Michael ◽  
Melina Sedano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Biology ◽  
Expression Patterns ◽  
Critical Role ◽  
Rna Seq ◽  
Cellular Processes ◽  
Er Positive ◽  
Intron Structure ◽  
Cancer Phenotypes ◽  
Underlying Mechanisms

Abstract Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cellular processes, but their roles in breast cancer biology are just beginning to be elucidated. In this study, integration of powerful techniques, RNA-seq data from subcellular fractionated RNA with GRO-seq data has yielded a comprehensive catalog of estrogen-regulated lncRNAs in MCF-7 cells. Analysis of RNA-seq data from samples representing molecular subtypes of breast cancer and normal tissue types, revealed that many lncRNAs (such as lincRNA86) show distinct expression patterns. LincRNA86 shows highest normal expression in pancreas followed by testis in normal human tissues. The hypothesis is lincRNA86 regulate estrogen-dependent signaling in breast cancer. In functional assays, knockdown of lncRNA86 inhibits the growth of ER-positive breast cancer cells. Amplified expression of lncRNA86 in breast cancer correlates with clinical outcome. LncRNA86 have now been fully annotated (transcription start and stop site, 5’ cap, polyA tail, and exon/intron structure), and cloned. We are now performing detailed molecular analyses to better understand the underlying mechanisms of action of the lncRNA. We are also currently have experiments underway to view cancer phenotypes: estrogen-dependent tumor growth. Collectively, our preliminary results suggest that lincRNA86 plays a critical role in ERα-dependent pathways.

scholarly journals Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review

2020 ◽  
Vol 21 (8) ◽  
pp. 3007 ◽  
Author(s):  
Amanda Fiore ◽  
Yue Liang ◽  
Yun Hsiao Lin ◽  
Jacky Tung ◽  
HanChen Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Current Knowledge ◽  
Cell Types ◽  
Histone H2a ◽  
Hematopoietic Stem ◽  
Developmental Abnormalities ◽  
Cellular Processes ◽  
Different Cell Types

MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human.

Long noncoding RNAs: lincs between human health and disease

2017 ◽  
Vol 45 (3) ◽  
pp. 805-812 ◽  
Author(s):  
Zhi Hao Kwok ◽  
Yvonne Tay
Keyword(s):  
Cancer Biology ◽  
High Throughput Sequencing ◽  
Current Knowledge ◽  
Noncoding Rnas ◽  
Clinical Applications ◽  
Long Noncoding Rnas ◽  
Cellular Processes ◽  
Health And Disease ◽  
Underlying Mechanisms ◽  
Sequencing Platforms

Long noncoding RNAs (lncRNAs) represent one of the largest classes of transcripts and are highly diverse in terms of characteristics and functions. Advances in high-throughput sequencing platforms have enabled the rapid discovery and identification of lncRNAs as key regulatory molecules involved in various cellular processes and their dysregulation in various human diseases. Here, we summarize the current knowledge of the functions and underlying mechanisms of lncRNA activity with a particular focus on cancer biology. We also discuss the potential of lncRNAs as diagnostic and therapeutic targets for clinical applications.

scholarly journals Regulatory network control of blood stem cells

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2614-2620 ◽  
Author(s):  
Berthold Göttgens
Keyword(s):  
Decision Making ◽  
Stem Cells ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Cell Types ◽  
Network Control ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Fate Decision ◽  
Underlying Mechanisms

Abstract Hematopoietic stem cells (HSCs) are characterized by their ability to execute a wide range of cell fate choices, including self-renewal, quiescence, and differentiation into the many different mature blood lineages. Cell fate decision making in HSCs, as indeed in other cell types, is driven by the interplay of external stimuli and intracellular regulatory programs. Given the pivotal nature of HSC decision making for both normal and aberrant hematopoiesis, substantial research efforts have been invested over the last few decades into deciphering some of the underlying mechanisms. Central to the intracellular decision making processes are transcription factor proteins and their interactions within gene regulatory networks. More than 50 transcription factors have been shown to affect the functionality of HSCs. However, much remains to be learned about the way in which individual factors are connected within wider regulatory networks, and how the topology of HSC regulatory networks might affect HSC function. Nevertheless, important progress has been made in recent years, and new emerging technologies suggest that the pace of progress is likely to accelerate. This review will introduce key concepts, provide an integrated view of selected recent studies, and conclude with an outlook on possible future directions for this field.

scholarly journals Functional Roles of Calreticulin in Cancer Biology

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yi-Chien Lu ◽  
Wen-Chin Weng ◽  
Hsinyu Lee
Keyword(s):  
Cell Adhesion ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Cell Types ◽  
Tumor Formation ◽  
Cancer Cell Proliferation ◽  
Transmembrane Receptors ◽  
Functional Roles ◽  
Cellular Processes ◽  
Endoplasmic Reticulum Chaperone

Calreticulin is a highly conserved endoplasmic reticulum chaperone protein which participates in various cellular processes. It was first identified as a Ca2+-binding protein in 1974. Accumulated evidences indicate that calreticulin has great impacts for the development of different cancers and the effect of calreticulin on tumor formation and progression may depend on cell types and clinical stages. Cell surface calreticulin is considered as an “eat-me” signal and promotes phagocytic uptake of cancer cells by immune system. Moreover, several reports reveal that manipulation of calreticulin levels profoundly affects cancer cell proliferation and angiogenesis as well as differentiation. In addition to immunogenicity and tumorigenesis, interactions between calreticulin and integrins have been described during cell adhesion, which is an essential process for cancer metastasis. Integrins are heterodimeric transmembrane receptors which connect extracellular matrix and intracellular cytoskeleton and trigger inside-out or outside-in signaling transduction. More and more evidences reveal that proteins binding to integrins might affect integrin-cytoskeleton interaction and therefore influence ability of cell adhesion. Here, we reviewed the biological roles of calreticulin and summarized the potential mechanisms of calreticulin in regulating mRNA stability and therefore contributed to cancer metastasis.

scholarly journals Single Cell Micro-Pillar-Based Characterization of Endothelial and Fibroblast Cell Mechanics

Micro ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 242-249
Author(s):  
Julia Eckert ◽  
Yasmine Abouleila ◽  
Thomas Schmidt ◽  
Alireza Mashaghi
Keyword(s):  
Single Cell ◽  
Force Measurement ◽  
Traction Force ◽  
Fibroblast Cell ◽  
Cell Types ◽  
Fibroblast Cells ◽  
Cellular Processes ◽  
Sense And Respond ◽  
Underlying Mechanisms

Mechanotransduction, the ability of cells to sense and respond to the mechanical cues from their microenvironment, plays an important role in numerous cellular processes, ranging from cell migration to differentiation. Several techniques have been developed to investigate the underlying mechanisms of mechanotransduction, in particular, force measurement-based techniques. However, we still lack basic single cell quantitative comparison on the mechanical properties of commonly used cell types, such as endothelial and fibroblast cells. Such information is critical to provide a precedent for studying complex tissues and organs that consist of various cell types. In this short communication, we report on the mechanical characterization of the commonly used endothelial and fibroblast cells at the single cell level. Using a micropillar-based assay, we measured the traction force profiles of these cells. Our study showcases differences between the two cell types in their traction force distribution and morphology. The results reported can be used as a reference and to lay the groundwork for future analysis of numerous disease models involving these cells.

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

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