Sphingolipids and Mitochondrial Dynamic

For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, in the present review, we focused on the relationship between sphingolipids, mainly ceramides and sphingosine-1-phosphate, and mitochondrial dynamics directed by fission, fusion, and mitophagy. There is evidence that the balances of ceramides (C18 and C16) and S1P, as well as the location of specific ceramide synthases in mitochondria, have roles in mitophagy and fission with an impact on cell fate and metabolism. However, signaling pathways controlling the sphingolipids metabolism and their location in mitochondria need to be better understood in order to propose new interventions and therapeutic strategies.

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Abstract 15178: Mitochondrial Dynamic Modulators Mitigates Mitochondrial Dynamic Index, Biogenesis and Metabolic Impairments in Prediabetic Rats With Cardiac Ischemia-reperfusion Injury

Circulation ◽

10.1161/circ.142.suppl_3.15178 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Chayodom Maneechote ◽

Siripong Palee ◽

Siriporn Chattipakorn ◽

Nipon CHATTIPAKORN

Keyword(s):

Lipid Metabolism ◽

Metabolic Pathway ◽

Chronic Treatment ◽

Metabolic Diseases ◽

Negative Impact ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Acute Administration ◽

Mitochondrial Dynamic ◽

Dynamic Index

Introduction: Long-term exposure to high-fat diet (HFD) caused obesity, which not only was positively associated with cardiovascular disorders but also had a negative impact on the outcome of acute myocardial ischemia-reperfusion (I/R) injury. Uncontrolled fission and diminished fusion of cardiac mitochondria augment the impairment of mitochondrial biogenesis and metabolism which have been implicated in metabolic diseases and I/R injury pathology. Since cardioprotective efficacy of acute administration of mitochondrial fission inhibitor (Mdivi-1) and fusion promoter (M1) have previously been reported, the effects of chronic treatment with both modulators on cardiac mitochondrial dynamics, biogenesis and lipid metabolism in prediabetic rats subjected to cardiac I/R injury have never been elucidated. Hypothesis: Chronic treatment of Mdivi-1 and M1 after acute myocardial I/R improve mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats. Methods: Male Wistar rats (n=18) were fed with HFD. After 12 weeks, all rats were randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMd (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection for 14 days. Then, all rats underwent 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 120 minutes. The expression of mitochondrial dynamics (p-Drp1 ser616 per Mfn2 ratio or dynamic index), biogenesis (PGC1- α) and lipid metabolism (CPT1) proteins from ischemic area of heart were determined. Results: Chronic treatment of Mdivi-1 and M1 similarly improved cardiac mitochondrial dynamic index (p-Drp1 ser616 per Mfn2 ratio), increased PGC1-α and CPT1 expression levels, when compared to HFV (Fig). Conclusions: Modulating mitochondrial dynamics by chronic treatment of Mdivi-1 and M1 improved cardiac mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats following acute myocardial I/R injury.

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Acid ceramidase, a double-edged sword in cancer aggression: A minireview

Current Cancer Drug Targets ◽

10.2174/1568009620666201223154621 ◽

2020 ◽

Vol 20 ◽

Author(s):

Helen Shiphrah Vethakanraj ◽

Niveditha Chandrasekaran ◽

Ashok Kumar Sekar

Keyword(s):

Cell Fate ◽

Cancer Progression ◽

Potential Role ◽

Tumour Progression ◽

Acid Ceramidase ◽

The Core ◽

The Past ◽

Sphingosine 1 Phosphate ◽

Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

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Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis

Cells ◽

10.3390/cells10123365 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3365

Author(s):

Gabriela Maria Guerra ◽

Doreen May ◽

Torsten Kroll ◽

Philipp Koch ◽

Marco Groth ◽

...

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Cortical Neurons ◽

Embryonic Stem ◽

Normal Structure ◽

Mutant Mice ◽

Cell Type ◽

Nonsense Mediated Mrna Decay ◽

A Cell ◽

Cell Type Specific

SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated Smg6 in murine embryonic neural stem cells. Nestin-Cre-mediated deletion of Smg6 in mouse neuroprogenitor cells (NPCs) caused perinatal lethality. Mutant mice brains showed normal structure at E14.5 but great reduction of the cortical NPCs and late-born cortical neurons during later stages of neurogenesis (i.e., E18.5). Smg6 inactivation led to dramatic cell death in ganglionic eminence (GE) and a reduction of interneurons at E14.5. Interestingly, neurosphere assays showed self-renewal defects specifically in interneuron progenitors but not in cortical NPCs. RT-qPCR analysis revealed that the interneuron differentiation regulators Dlx1 and Dlx2 were reduced after Smg6 deletion. Intriguingly, when Smg6 was deleted specifically in cortical and hippocampal progenitors, the mutant mice were viable and showed normal size and architecture of the cortex at E18.5. Thus, SMG6 regulates cell fate in a cell type-specific manner and is more important for neuroprogenitors originating from the GE than for progenitors from the cortex.

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Abstract P049: Circadian Clock Dysfunction Impairs Mitochondrial Fitness And Contributes To Myocardial Ischemic Injury

Hypertension ◽

10.1161/hyp.76.suppl_1.p049 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Inna Rabinovich-Nikitin ◽

Illana Posen ◽

Victoria Margulets ◽

Tami A Martino ◽

Lorrie A Kirshenbaum

Keyword(s):

Quality Control ◽

Cell Viability ◽

Circadian Clock ◽

Cardiac Myocytes ◽

Mitochondrial Dynamics ◽

Ischemia Reperfusion ◽

Mitochondrial Fission ◽

Control Mechanisms ◽

Complex Activity ◽

Mitochondrial Dynamic

Cardiac function is highly reliant on mitochondrial oxidative metabolism and fitness. The circadian clock is critically linked to vital physiological process including mitochondrial fission, fusion and quality control mechanisms. However, little is known of how the circadian clock regulates these vital processes in the heart. Herein, we identified a putative circadian Clock - mitochondrial interactome that gates an adaptive stress response for cell viability during myocardial ischemia reperfusion (I-R) injury. We show that Clock transcriptionally coordinates expression of mitochondrial dynamic fusion and fission, bioenergetic and quality control proteins in cardiac myocytes. Transcriptome and gene ontology mapping revealed Clock defective hearts subjected to I-R exhibited major transcriptional deficits in several key survival processes including mitochondrial dynamics, bioenergetics and autophagy that were reduced further following I-R. Gain of function of Clock activity re-established gene transcription of mitochondrial respiratory complex activity, quality control mechanisms and cell viability. Collectively, our data show that mitochondrial fitness and cell survival is mutually dependent upon and obligatorily linked to transcription of the circadian Clock gene in cardiac myocytes. Our data suggest the functional loss of Clock activity predisposes cardiac myocytes to metabolic catastrophe. Hence, therapeutic strategies designed to preserve circadian clock activity in the hearts may prove beneficial in reducing morbidity and mortality following ischemia -related pathologies such as myocardial infarction.

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FOXO transcription factor family in cancer and metastasis

Cancer and Metastasis Reviews ◽

10.1007/s10555-020-09883-w ◽

2020 ◽

Vol 39 (3) ◽

pp. 681-709 ◽

Cited By ~ 2

Author(s):

Yannasittha Jiramongkol ◽

Eric W.-F. Lam

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Gene Networks ◽

Cancer Metastasis ◽

Metabolic Diseases ◽

Genetic Disorders ◽

Primary Tumour ◽

Control Cell ◽

Normal Tissues ◽

Foxo Transcription Factors

Abstract Forkhead box O (FOXO) transcription factors regulate diverse biological processes, affecting development, metabolism, stem cell maintenance and longevity. They have also been increasingly recognised as tumour suppressors through their ability to regulate genes essential for cell proliferation, cell death, senescence, angiogenesis, cell migration and metastasis. Mechanistically, FOXO proteins serve as key connection points to allow diverse proliferative, nutrient and stress signals to converge and integrate with distinct gene networks to control cell fate, metabolism and cancer development. In consequence, deregulation of FOXO expression and function can promote genetic disorders, metabolic diseases, deregulated ageing and cancer. Metastasis is the process by which cancer cells spread from the primary tumour often via the bloodstream or the lymphatic system and is the major cause of cancer death. The regulation and deregulation of FOXO transcription factors occur predominantly at the post-transcriptional and post-translational levels mediated by regulatory non-coding RNAs, their interactions with other protein partners and co-factors and a combination of post-translational modifications (PTMs), including phosphorylation, acetylation, methylation and ubiquitination. This review discusses the role and regulation of FOXO proteins in tumour initiation and progression, with a particular emphasis on cancer metastasis. An understanding of how signalling networks integrate with the FOXO transcription factors to modulate their developmental, metabolic and tumour-suppressive functions in normal tissues and in cancer will offer a new perspective on tumorigenesis and metastasis, and open up therapeutic opportunities for malignant diseases.

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T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽

10.3390/toxins12010043 ◽

2020 ◽

Vol 12 (1) ◽

pp. 43 ◽

Cited By ~ 5

Author(s):

Junhua Yang ◽

Wenbo Guo ◽

Jianhua Wang ◽

Xianli Yang ◽

Zhiqi Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Apoptosis ◽

Human Liver ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Fusion ◽

Mitochondrial Dynamic ◽

Normal Human Liver ◽

Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

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The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

Mediators of Inflammation ◽

10.1155/2017/4806541 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 52

Author(s):

Nitai C. Hait ◽

Aparna Maiti

Keyword(s):

Cell Growth ◽

Cell Fate ◽

Cancer Progression ◽

Tissue Injury ◽

Cell Types ◽

Cancer Cell Growth ◽

Ceramide Level ◽

Cytokines And Chemokines ◽

Sphingosine 1 Phosphate ◽

Ceramide 1

Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

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Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells

Cancers ◽

10.3390/cancers12061643 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1643

Author(s):

Sandy Anania ◽

Raphaël Peiffer ◽

Gilles Rademaker ◽

Alexandre Hego ◽

Marc Thiry ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Pancreas Cancer ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Cancer Cell Lines ◽

Ductal Adenocarcinoma ◽

Mitochondrial Dynamic ◽

Pancreatic Cancer Cells

Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer.

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United colours of chromatin? Developmental genome organisation in flies

Biochemical Society Transactions ◽

10.1042/bst20180605 ◽

2019 ◽

Vol 47 (2) ◽

pp. 691-700

Author(s):

Caroline Delandre ◽

Owen J. Marshall

Keyword(s):

Cell Fate ◽

Fruit Fly ◽

Genome Organisation ◽

Chromatin Protein ◽

Cell Type ◽

Chromatin States ◽

Cell Fate Decisions ◽

A Cell ◽

Cell Type Specific ◽

Chromatin Biology

Abstract The organisation of DNA into differing forms of packaging, or chromatin, controls many of the cell fate decisions during development. Although early studies focused on individual forms of chromatin, in the last decade more holistic studies have attempted to determine a complete picture of the different forms of chromatin present within a cell. In the fruit fly, Drosophila melanogaster, the study of chromatin states has been aided by the use of complementary and cell-type-specific techniques that profile the marks that recruit chromatin protein binding or the proteins themselves. Although many questions remain unanswered, a clearer picture of how different chromatin states affect development is now emerging, with more unusual chromatin states such as Black chromatin playing key roles. Here, we discuss recent findings regarding chromatin biology in flies.

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Resveratrol Targets Sphingolipid Metabolism to Induce Growth Inhibition in FLT3 ITD Acute Myeloid Leukemia

Proceedings ◽

10.3390/proceedings2019040004 ◽

2019 ◽

Vol 40 (1) ◽

pp. 4

Author(s):

Ersöz ◽

Adan

Keyword(s):

Growth Inhibition ◽

Cell Fate ◽

De Novo ◽

Therapeutic Potential ◽

Annexin V ◽

Sphingolipid Metabolism ◽

Ceramide Synthase ◽

Cytotoxic Effects ◽

Sphingosine 1 Phosphate ◽

First Time

Sphingolipids are important signaling lipids which play crucial roles to determine the cell fate. Ceramide, apoptotic central molecule of sphingolipid metabolism, which is produced through de novo pathway by serine palmitoyl transferase (SPT) and can be converted to antiapoptotic sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3-ITD (Internal Tandem Duplication) AML cells and to identify potential mechanism behind resveratrol-mediated growth inhibition by targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SPT inhibitor (myricoin), SK-1 inhibitor (SKI II), GCS inhibitor (PDMP), resveratrol: SPT inhibitor, resveratrol: SK-1 inhibitor and resveratrol: GCS inhibitor combinations on MOLM-13 and MV4-11 FLT3 ITD AML cells were investigated by cell proliferation assay. Apoptosis was evaluated by annexin V/PI double staining. There were synergistic cytotoxic effects of resveratrol with co-administration of SPT inhibitor, SK-1 inhibitor and GCS inhibitor and apoptosis was synergistically induced for resveratrol and its combinations. This preliminary data showed for the first time that resveratrol might inhibit the growth of FLT3 ITD AML cells through targeting ceramide metabolism.

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