scholarly journals Human blood-derived lymphoblastoid cybrids for assessment of mitochondrial tRNAs deficiency by MTO1 silence

2021 ◽  
Author(s):  
Qi Wang ◽  
Maerhaba Aishanjiang ◽  
Yuping Wei ◽  
Zewen Gao ◽  
Ye Chen ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Functional Role ◽  
Cardiac Tissue ◽  
White Blood Cells ◽  
High Energy ◽  
Mitochondrial Translation ◽  
Protein Levels ◽  
Energy Demands ◽  
Translation Optimization

Abstract Mutations in the mitochondrial translation optimization 1 (MTO1) gene can cause hypertrophic cardiomyopathy. Although the functional role of MTO1 deficiency in certain cells is gradually confirmed, the phenotype of MTO1 deficiency in a lymphoblastoid cybrid line is not yet reported. In this study, we characterized changes of mitochondrial function in MTO1 silenced cybrid cells derived from human lymphoblastoids, immature white blood cells that give rise to lymphocytes. We showed that MTO1 silence decreased the levels of 2-thiourylation of mitochondrial tRNALys, tRNAGlu, and tRNAGln, nevertheless, the aminoacylation efficiency of tRNALys and the steady state of mitochondrial tRNAs were elevated. These aberrant tRNA changes caused a significant decrease in protein levels of oxidative phosphorylation complex subunits including complex I, III, IV and V. Furthermore, dysfunctional mitochondria promoted apoptosis in stress, evidenced by elevated ratios of apoptotic cells and increased levels of apoptosis-activated proteins in the MTO1 knockdown cell lines, as compared to the controls. Our data provide new insights into the important functional role of MTO1 in lymphoblastoid mitochondria. We envision the cybrid cell line approach we have established provides an alternative model for the cardiac tissue of high-energy demands characteristics, and they hold promises for the diagnosis and drug screening for the therapeutic agents of hypertrophic cardiomyopathy caused by MTO1 dysfunction.

scholarly journals Human Blood-Derived Lymphoblastoid Cybrids for Assessment of Mitochondrial tRNAs Deficiency by MTO1 Silence

2021 ◽  
Author(s):  
Chao Chen ◽  
Qi Wang ◽  
Maerhaba Aishanjiang ◽  
Yuping Wei ◽  
Zewen Gao ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Functional Role ◽  
Cardiac Tissue ◽  
White Blood Cells ◽  
High Energy ◽  
Mitochondrial Translation ◽  
Protein Levels ◽  
Energy Demands ◽  
Translation Optimization

Abstract Background: Mutations in the mitochondrial translation optimization 1 (MTO1) gene can cause hypertrophic cardiomyopathy. Although the functional role of MTO1 deficiency in certain cells is gradually confirmed, the phenotype of MTO1 deficiency in a lymphoblastoid cybrid line is not yet reported. In this study, we characterized changes of mitochondrial function in MTO1 silenced cybrid cells derived from human lymphoblastoids, immature white blood cells that give rise to lymphocytes. Results: We showed that MTO1 silence decreased the levels of 2-thiourylation of mitochondrial tRNALys, tRNAGlu, and tRNAGln, nevertheless, the aminoacylation efficiency of tRNALys and the steady state of mitochondrial tRNAs were elevated. These aberrant tRNA changes caused a significant decrease in protein levels of oxidative phosphorylation complex subunits including complex I, III, IV and V. Furthermore, dysfunctional mitochondria promoted apoptosis in stress, evidenced by elevated ratios of apoptotic cells and increased levels of apoptosis-activated proteins in the MTO1 knockdown cell lines, as compared to the controls. Conclusions: Our data provide new insights into the important functional role of MTO1 in lymphoblastoid mitochondria. We envision the cybrid cell line approach we have established provides an alternative model for the cardiac tissue of high-energy demands characteristics, and they hold promises for the diagnosis and drug screening for the therapeutic agents of hypertrophic cardiomyopathy caused by MTO1 dysfunction.

Workshop no. 1. Alternate metabolic pathways in protozoan energy metabolism

Parasitology ◽  
1981 ◽  
Vol 82 (4) ◽  
pp. 1-30 ◽  
Keyword(s):  
Energy Metabolism ◽  
Metabolic Pathways ◽  
Functional Role ◽  
High Energy ◽  
Strictly Anaerobic ◽  
Factors Affecting ◽  
Subcellular Compartmentation ◽  
Similarities And Differences ◽  
Metabolic Behaviour

The purpose of this workshop was to collect together colleagues investigating the intermediary metabolism of protozoa, with a view to discussing those pathways involved in energy metabolism and the production of ATP and other high-energy compounds, together with the factors affecting energy balance. The aspects of energy metabolism chosen for discussion comprised the metabolic pathways ranging from the strictly anaerobic to highly oxidative; subcellular compartmentation of these pathways within the protozoa; the functional role of these pathways including a consideration of aero-tolerance; and the use of inhibitors as biochemical probes and potential chemotherapeuticagents. Hopefully this approach has produced a broad 'over-view' of important areas of protozoan energy metabolism which will enable both the specialist and non-specialist to appreciate the similarities and differences between the metabolic behaviour of a range of protozoa.

scholarly journals Peroxisome extensions deliver the Arabidopsis SDP1 lipase to oil bodies

2015 ◽  
Vol 112 (13) ◽  
pp. 4158-4163 ◽  
Author(s):  
Nelcy Thazar-Poulot ◽  
Martine Miquel ◽  
Isabelle Fobis-Loisy ◽  
Thierry Gaude
Keyword(s):  
Protein Trafficking ◽  
Protein Transport ◽  
Energy Resource ◽  
High Energy ◽  
Eukaryotic Cells ◽  
Oil Bodies ◽  
Energy Demands ◽  
Lipid Store ◽  
Lipid Stores

Lipid droplets/oil bodies (OBs) are lipid-storage organelles that play a crucial role as an energy resource in a variety of eukaryotic cells. Lipid stores are mobilized in the case of food deprivation or high energy demands—for example, during certain developmental processes in animals and plants. OB degradation is achieved by lipases that hydrolyze triacylglycerols (TAGs) into free fatty acids and glycerol. In the model plant Arabidopsis thaliana, Sugar-Dependent 1 (SDP1) was identified as the major TAG lipase involved in lipid reserve mobilization during seedling establishment. Although the enzymatic activity of SDP1 is associated with the membrane of OBs, its targeting to the OB surface remains uncharacterized. Here we demonstrate that the core retromer, a complex involved in protein trafficking, participates in OB biogenesis, lipid store degradation, and SDP1 localization to OBs. We also report an as-yet-undescribed mechanism for lipase transport in eukaryotic cells, with SDP1 being first localized to the peroxisome membrane at early stages of seedling growth and then possibly moving to the OB surface through peroxisome tubulations. Finally, we show that the timely transfer of SDP1 to the OB membrane requires a functional core retromer. In addition to revealing previously unidentified functions of the retromer complex in plant cells, our work provides unanticipated evidence for the role of peroxisome dynamics in interorganelle communication and protein transport.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes

2014 ◽  
Vol 92 (8) ◽  
pp. 703-706 ◽  
Author(s):  
David Z.I. Cherney ◽  
Fengxia Xiao ◽  
Joseph Zimpelmann ◽  
Ronnie L.H. Har ◽  
Vesta Lai ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Enzyme Activity ◽  
Angiotensin Converting Enzyme ◽  
Functional Role ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Levels ◽  
Clinical Complications

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4–6 mmol·L–1) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9–11 mmol·L–1) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

scholarly journals Cardiac Tissue Factor Regulates Inflammation, Hypertrophy and Heart Failure in Mouse Model of Type 1 Diabetes

2021 ◽  
Author(s):  
Dasan Mary Cibi ◽  
Reddemma Sandireddy ◽  
Hanumakumar Bogireddy ◽  
Nicole Tee ◽  
Siti Aishah Binte Abdul Ghani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Tissue Factor ◽  
Cardiac Tissue ◽  
Immune Cell ◽  
Preserved Ejection Fraction ◽  
Cardiac Inflammation ◽  
Protein Levels ◽  
Increased Risk

Diabetes patients have an increased risk of heart failure (HF). Diabetes is highly prevalent in HF with preserved ejection fraction (HFpEF), which is on the rise worldwide. The role of diabetes in HF is less established and available treatments of HF are not effective in HFpEF patients. Tissue factor (TF), a transmembrane receptor, plays an important role in immune-cell inflammation and atherothrombosis in diabetes. However, its role in diabetes-induced cardiac inflammation, hypertrophy, and HF has not been studied. Here, we have utilized Wildtype (WT), heterozygous, and Low-TF (with 1% human TF) mice to determine TF’s role in <i>Type1 diabetes</i>-induced HF. We found significant upregulation of cardiac TF mRNA and protein levels in diabetic WT hearts compared to non-diabetic controls. WT diabetic hearts also exhibited increased inflammation and cardiac hypertrophy versus controls. However, these changes in cardiac inflammation and hypertrophy were not found in diabetic Low-TF mice compared to their non-diabetic controls. TF deficiency was also associated with improved cardiac function parameters suggestive of HFpEF, which was evident in diabetic WT mice. The TF regulation of inflammation and cardiac remodeling was further dependent on downstream ERK1/2 and STAT3 pathways. In summary, our study demonstrated an important role of TF in regulating diabetes-induced inflammation, hypertrophy, and remodeling of the heart leading to HF with preserved ejection fraction.

scholarly journals Oligodendrocyte Bioenergetics in Health and Disease

2018 ◽  
Vol 25 (4) ◽  
pp. 334-343 ◽  
Author(s):  
Lauren Rosko ◽  
Victoria N. Smith ◽  
Reiji Yamazaki ◽  
Jeffrey K. Huang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Energy ◽  
The Body ◽  
Metabolic Coupling ◽  
Energy Demands ◽  
Metabolic Role ◽  
The Central Nervous System ◽  
The Impact

The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person’s total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.

scholarly journals Mitochondrial dynamics during spermatogenesis

2020 ◽  
Vol 133 (14) ◽  
pp. jcs235937
Author(s):  
Grigor Varuzhanyan ◽  
David C. Chan
Keyword(s):  
Germ Line ◽  
Mitochondrial Dynamics ◽  
High Energy ◽  
Mitochondrial Fusion ◽  
Developmental Systems ◽  
Developmentally Regulated ◽  
Energy Demands ◽  
Normal Cellular Function

ABSTRACTMitochondrial fusion and fission (mitochondrial dynamics) are homeostatic processes that safeguard normal cellular function. This relationship is especially strong in tissues with constitutively high energy demands, such as brain, heart and skeletal muscle. Less is known about the role of mitochondrial dynamics in developmental systems that involve changes in metabolic function. One such system is spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. In mammals, however, the role of mitochondrial fusion during spermatogenesis remained unknown for nearly two decades after discovery of Fzo. Mammalian spermatogenesis is one of the most complex and lengthy differentiation processes in biology, transforming spermatogonial stem cells into highly specialized sperm cells over a 5-week period. This elaborate differentiation process requires several developmentally regulated mitochondrial and metabolic transitions, making it an attractive model system for studying mitochondrial dynamics in vivo. We review the emerging role of mitochondrial biology, and especially its dynamics, during the development of the male germ line.

scholarly journals Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristina Sonnenschein ◽  
Jan Fiedler ◽  
David de Gonzalo-Calvo ◽  
Ke Xiao ◽  
Angelika Pfanne ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Serum Protein ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Protein Profiling ◽  
Healthy Population ◽  
Healthy Controls ◽  
Protein Levels

AbstractHypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.

scholarly journals Role of Filamentous Phage SW1 in Regulating the Lateral Flagella of Shewanella piezotolerans Strain WP3 at Low Temperatures

2013 ◽  
Vol 79 (22) ◽  
pp. 7101-7109 ◽  
Author(s):  
Huahua Jian ◽  
Xiang Xiao ◽  
Fengping Wang
Keyword(s):  
Deep Sea ◽  
Low Temperatures ◽  
High Energy ◽  
Filamentous Phage ◽  
Swarming Motility ◽  
Content Type ◽  
Energy Demands ◽  
Solid Agar ◽  
Whole Genome Microarray

ABSTRACTLow-temperature ecosystems represent the largest biosphere on Earth, and yet our understanding of the roles of bacteriophages in these systems is limited. Here, the influence of the cold-active filamentous phage SW1 on the phenotype and gene transcription of its host,Shewanella piezotoleransWP3 (WP3), was investigated by construction of a phage-free strain (WP3ΔSW1), which was compared with the wild-type strain. The expression of 49 genes, including 16 lateral flagellar genes, was found to be significantly influenced by SW1 at 4°C, as demonstrated by comparative whole-genome microarray analysis. WP3ΔSW1 was shown to have a higher production of lateral flagella than WP3 and enhanced swarming motility when cultivated on solid agar plates. Besides, SW1 has a remarkable impact on the expression of a variety of host genes in liquid culture, particularly the genes related to the membrane and to the production of lateral flagella. These results suggest that the deep-sea bacterium WP3 might balance the high-energy demands of phage maintenance and swarming motility at low temperatures. The phage SW1 is shown to have a significant influence on the swarming ability of the host and thus may play an important role in adjusting the fitness of the cells in the deep-sea environment.

scholarly journals Functional and Clinical Relevance of Splicing Factor SRSF1 in Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3388-3388
Author(s):  
Mariateresa Fulciniti ◽  
Manoj Bhasin ◽  
Mehmet Kemal Samur ◽  
Rajya Lakshmi Bandi ◽  
Naim Rashid ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Functional Role ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Splicing Factor ◽  
Splicing Factors ◽  
Related Factors ◽  
Protein Levels ◽  
Significant Difference

Abstract The mechanisms modifying expression and function of genes, such as alternative pre-mRNA splicing or microRNA (miRNA) activity, need to be considered in order to provide a more accurate genomic framework for clinical correlation, as well as for high value therapeutic target discovery. Aberrant splicing of numerous genes has been reported in other malignancies, including a small number of genes reported in MM. The emerging focus therefore, has been to understand the molecular mechanisms driving alternate splicing. Several studies provide evidence that an abnormally expressed splicing factor can have oncogenic properties by impacting alternative splicing of cancer-associated genes. Based on our previously described significant role of E2F1 and its heterodimerization partner Dp1 in myeloma, we evaluated their chromatin binding targets related with splicing factors. Using genome wide chromatin and transcription landscape mapping techniques, we observed both transcription factors bound to the promoter of several splicing factors including Serine Arginine-Rich Splicing Factor 1 (SRSF1). Further evaluation in our gene expression profile from 170 newly-diagnosed myeloma patients, identified high expression of SRSF1 in MM compared to normal plasma cells, with a significant difference in the non-hyperdiploid subtype. Importantly, we have observed significant coexpression of Dp1 and SRSF1 in this dataset suggesting a mechanism for SRSF1 upregulation in tumors with elevated Dp1. SRSF1 has been shown to be overexpressed in human tumors with elevated Myc. No correlation between Myc with SRSF1 was observed in myeloma suggesting that SRSF1 expression is mediated by Myc-independent mechanism. We next explored the functional role of SRSF1 in MM. In gain-of-function experiments, enforced expression of SRSF1-eGFP in MM1S significantly increased proliferation. Conversely, downregulation of SRSF1 with specific shRNAs in MM cell lines significantly inhibited MM cell proliferation and cell survival. These data underscore the oncogenic potential of SRSF1 in MM. A significant reduction in SRSF1 at mRNA and protein levels was observed after E2F1 and/or Dp1 gene silencing. Moreover, peptide-based strategy to abrogate interaction between Dp1-E2F1 led to decreased SRSF1 expression levels. Importantly, the increased expression of SRSF1 was linked with overall survival in 2 independent MM datasets, highlighting for the first time the clinical relevance of splicing related factors in myeloma. In conclusion our results indicate a functional role and clinical significance of a gene involved in regulation of gene splicing. This study highlights the need to further understand the splicing pattern in myeloma and also supports the emerging concept that splicing programs, together with transcriptional programs participate in the altered cellular function during tumor initiation and progression. Disclosures Anderson: Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

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