The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis

AbstractBackgroundThe molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other.ResultsWe show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline or an increase in OXPHOS.ConclusionsOur work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

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Colorectal cancers utilize glutamine as an anaplerotic substrate of the TCA cycle in vivo

Scientific Reports ◽

10.1038/s41598-019-55718-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Yiqing Zhao ◽

Xuan Zhao ◽

Vanessa Chen ◽

Ying Feng ◽

Lan Wang ◽

...

Keyword(s):

Tca Cycle ◽

Genetically Engineered ◽

Glutamine Metabolism ◽

Colorectal Cancers ◽

Wild Type ◽

Colon Tumors ◽

The Tca Cycle ◽

Genetically Engineered Mice ◽

Tca Cycle Intermediates

AbstractCancer cells in culture rely on glutamine as an anaplerotic substrate to replenish tricarboxylic acid (TCA) cycle intermediates that have been consumed. but it is uncertain whether cancers in vivo depend on glutamine for anaplerosis. Here, following in vivo infusions of [13C5]-glutamine in mice bearing subcutaneous colon cancer xenografts, we showed substantial amounts of infused [13C5]-glutamine enters the TCA cycle in the tumors. Consistent with our prior observation that colorectal cancers (CRCs) with oncogenic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic (PIK3CA) subunit are more dependent on glutamine than CRCs with wild type PIK3CA, labeling from glutamine to most TCA cycle intermediates was higher in PIK3CA-mutant subcutaneous xenograft tumors than in wild type PIK3CA tumors. Moreover, using orthotopic mouse colon tumors estalished from human CRC cells or patient-derived xenografts, we demonstrated substantial amounts of infused [13C5]-glutamine enters the TCA cycle in the tumors and tumors utilize anaplerotic glutamine to a greater extent than adjacent normal colon tissues. Similar results were seen in spontaneous colon tumors arising in genetically engineered mice. Our studies provide compelling evidence CRCs utilizes glutamine to replenish the TCA cycle in vivo, suggesting that targeting glutamine metabolism could be a therapeutic approach for CRCs, especially for PIK3CA-mutant CRCs.

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Ins and Outs of the TCA Cycle: The Central Role of Anaplerosis

Annual Review of Nutrition ◽

10.1146/annurev-nutr-120420-025558 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Melissa Inigo ◽

Stanisław Deja ◽

Shawn C. Burgess

Keyword(s):

Redox State ◽

Tca Cycle ◽

Oxidative Capacity ◽

Annual Review ◽

Publication Date ◽

Energy Status ◽

Cellular Energy ◽

The Tca Cycle ◽

Tca Cycle Intermediates

The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status. They facilitate recycling pathways and nitrogen trafficking necessary for catabolism, and they influence redox state and oxidative capacity by altering TCA cycle intermediate concentrations. These functions vary widely by tissue and play emerging roles in disease. This article reviews the roles of anaplerosis and cataplerosis in various tissues and discusses how they alter carbon transitions, and highlights their contribution to mechanisms of disease. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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TAMI-42. H3K27M MUTANT GLIOMAS HIJACK A CONSERVED AND CRITICAL METABOLIC PATHWAY USED BY IDH1 MUTANT GLIOMAS TO MAINTAIN THEIR PREFERRED EPIGENETIC STATE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.930 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii222-ii222

Author(s):

Chan Chung ◽

Stefan Sweha ◽

Drew Pratt ◽

Benita Tamrazi ◽

Pooja Panwalkar ◽

...

Keyword(s):

Glutamate Dehydrogenase ◽

Metabolic Pathway ◽

Tca Cycle ◽

Chromatin Accessibility ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Wild Type ◽

Hexokinase 2

Abstract H3K27M-midline gliomas are fatal tumors that mainly harbor H3.3K27M mutations resulting in global H3K27me3 reduction that impacts neuroglial-differentiation. However, the exact mechanisms by which H3.3K27M mutations promote cancer are poorly understood. Metabolic reprogramming is a hallmark of cancer and we hypothesized that H3.3K27M mutations can reprogram metabolism to support uncontrolled growth. We demonstrate that H3.3K27M-mutant cells show elevated levels of critical enzymes related to glycolysis and TCA cycle metabolism including hexokinase-2, isocitrate dehydrogenase (IDH)-1 and glutamate dehydrogenase. H3.3K27M cells also demonstrated enhanced glycolysis, glutamine and TCA-cycle metabolism accompanied by increased alpha-ketoglutarate (α-KG) production. Mutant IDH (mIDH)1/2 converts α-KG to D-2-hydroxyglutarate (D-2HG). D-2HG increases H3K27me3 by inhibiting α-KG’s function to drive H3K27-demethylases. We discovered that H3.3K27M cells use α-KG in an opposing manner to maintain low H3K27me3. Inhibiting enzymes related to α-KG generation including hexokinase-2, glutamate-dehydrogenase and wild type-IDH1 increased global H3K27me3, altered chromatin accessibility at neuroglial-differentiation factors and lowered tumor cell proliferation. In vivo inhibition of glutamine metabolism and/ or wild type-IDH1 using blood-brain barrier penetrant small molecule inhibitors increased overall survival in vivo in two independent H3.3K27M animal models (p< 0.0001). H3K27M and mIDH1 were mutually exclusive in patient tumor samples and D-2HG treatment or forced-mIDH1 expression in H3.3K27M cells increased global H3K27me3 and cell death. Finally H3.3K27M and mIDH1 were synthetic lethal in vitro. Our data suggest that H3.3K27M and mIDH1 hijack a critical and conserved metabolic pathway in opposing manners to regulate global H3K27me3. These results have implications for understanding the pathogenesis of fatal H3K27M-gliomas and for developing therapeutic strategies by disruption of an integrated metabolic/epigenetic-axis.

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Synthesis and Breakdown of the Universal Precursors to Biological Metabolism Promoted by Ferrous Iron

10.26434/chemrxiv.7178930.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Kamila B. Muchowska ◽

Sreejith Jayasree VARMA ◽

Joseph Moran

Keyword(s):

Amino Acids ◽

Chemical Reaction ◽

Metabolic Pathways ◽

Ferrous Iron ◽

Reaction Network ◽

Tca Cycle ◽

Chemical Reaction Network ◽

Metabolic Precursors ◽

Tca Cycle Intermediates

How core biological metabolism initiated and why it uses the intermediates, reactions and pathways that it does remains unclear. Life builds its molecules from CO2 and breaks them down to CO2 again through the intermediacy of just five metabolites that act as the hubs of biochemistry. Here, we describe a purely chemical reaction network promoted by Fe2+ in which aqueous pyruvate and glyoxylate, two products of abiotic CO2 reduction, build up nine of the eleven TCA cycle intermediates, including all five universal metabolic precursors. The intermediates simultaneously break down to CO2 in a life-like regime resembling biological anabolism and catabolism. Introduction of hydroxylamine and Fe0 produces four biological amino acids. The network significantly overlaps the TCA/rTCA and glyoxylate cycles and may represent a prebiotic precursor to these core metabolic pathways.

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Effects of Liver Cancer Drugs on Cellular Energy Metabolism in Hepatocellular Carcinoma Cells

International Journal of Pharmaceutical Research ◽

10.31838/ijpr/2018.10.03.079 ◽

2018 ◽

Vol 10 (03) ◽

Keyword(s):

Hepatocellular Carcinoma ◽

Energy Metabolism ◽

Liver Cancer ◽

Carcinoma Cells ◽

Cancer Drugs ◽

Hepatocellular Carcinoma Cells ◽

Cellular Energy ◽

Cellular Energy Metabolism

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Faculty Opinions recommendation of Atoms to phenotypes: molecular design principles of cellular energy metabolism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736905349.793567450 ◽

2019 ◽

Author(s):

Miguel Teixeira

Keyword(s):

Energy Metabolism ◽

Molecular Design ◽

Design Principles ◽

Cellular Energy ◽

Cellular Energy Metabolism

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Profiles of Secondary Metabolites (Phenolic Acids, Carotenoids, Anthocyanins, and Galantamine) and Primary Metabolites (Carbohydrates, Amino Acids, and Organic Acids) during Flower Development in Lycoris radiata

Biomolecules ◽

10.3390/biom11020248 ◽

2021 ◽

Vol 11 (2) ◽

pp. 248

Author(s):

Chang Ha Park ◽

Hyeon Ji Yeo ◽

Ye Jin Kim ◽

Bao Van Nguyen ◽

Ye Eun Park ◽

...

Keyword(s):

Amino Acids ◽

Secondary Metabolites ◽

Organic Acids ◽

Phenolic Acids ◽

Flower Development ◽

Developmental Stages ◽

Tca Cycle ◽

Primary And Secondary Metabolites ◽

Hydrophilic Compounds ◽

Tca Cycle Intermediates

This study aimed to elucidate the variations in primary and secondary metabolites during Lycorisradiata flower development using high performance liquid chromatography (HPLC) and gas chromatography time-of-flight mass spectrometry (GC-TOFMS). The result showed that seven carotenoids, seven phenolic acids, three anthocyanins, and galantamine were identified in the L. radiata flowers. Most secondary metabolite levels gradually decreased according to the flower developmental stages. A total of 51 metabolites, including amines, sugars, sugar intermediates, sugar alcohols, amino acids, organic acids, phenolic acids, and tricarboxylic acid (TCA) cycle intermediates, were identified and quantified using GC-TOFMS. Among the hydrophilic compounds, most amino acids increased during flower development; in contrast, TCA cycle intermediates and sugars decreased. In particular, glutamine, asparagine, glutamic acid, and aspartic acid, which represent the main inter- and intracellular nitrogen carriers, were positively correlated with the other amino acids and were negatively correlated with the TCA cycle intermediates. Furthermore, quantitation data of the 51 hydrophilic compounds were subjected to partial least-squares discriminant analyses (PLS-DA) to assess significant differences in the metabolites of L. radiata flowers from stages 1 to 4. Therefore, this study will serve as the foundation for a biochemical approach to understand both primary and secondary metabolism in L. radiata flower development.

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Cytochrome c Deficiency Differentially Affects the In Vivo Mitochondrial Electron Partitioning and Primary Metabolism Depending on the Photoperiod

Plants ◽

10.3390/plants10030444 ◽

2021 ◽

Vol 10 (3) ◽

pp. 444

Author(s):

Igor Florez-Sarasa ◽

Elina Welchen ◽

Sofia Racca ◽

Daniel H. Gonzalez ◽

José G. Vallarino ◽

...

Keyword(s):

Cytochrome C ◽

Tca Cycle ◽

Day Length ◽

Primary Metabolism ◽

Stress Signaling ◽

Alternative Pathways ◽

Tca Cycle Intermediates ◽

Growth Adaptation ◽

Plant Respiration

Plant respiration provides metabolic flexibility under changing environmental conditions by modulating the activity of the nonphosphorylating alternative pathways from the mitochondrial electron transport chain, which bypass the main energy-producing components of the cytochrome oxidase pathway (COP). While adjustments in leaf primary metabolism induced by changes in day length are well studied, possible differences in the in vivo contribution of the COP and the alternative oxidase pathway (AOP) between different photoperiods remain unknown. In our study, in vivo electron partitioning between AOP and COP and expression analysis of respiratory components, photosynthesis, and the levels of primary metabolites were studied in leaves of wild-type (WT) plants and cytochrome c (CYTc) mutants, with reduced levels of COP components, under short- and long-day photoperiods. Our results clearly show that differences in AOP and COP in vivo activities between WT and cytc mutants depend on the photoperiod likely due to energy and stress signaling constraints. Parallel responses observed between in vivo respiratory activities, TCA cycle intermediates, amino acids, and stress signaling metabolites indicate the coordination of different pathways of primary metabolism to support growth adaptation under different photoperiods.

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Targeting Mitochondria in Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms22126642 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6642

Author(s):

Nina Krako Jakovljevic ◽

Kasja Pavlovic ◽

Aleksandra Jotic ◽

Katarina Lalic ◽

Milica Stoiljkovic ◽

...

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Whole Body ◽

Noncommunicable Diseases ◽

Pharmacological Interventions ◽

Cellular Energy ◽

Cellular Energy Metabolism ◽

Data Comparison ◽

Selection Of

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

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