Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects

Tyrakis, Petros A.; Yurkovich, Marie E.; Sciacovelli, Marco; Papachristou, Evangelia K.; Bridges, Hannah R.; Gaude, Edoardo; Schreiner, A.; D’Santos, Clive S.; Hirst, Judy; Hernández-Fernaud, Juan R.; Springett, Roger; Griffiths, John R.; Frezza, Christian

doi:10.1016/j.celrep.2017.09.092

Cited by 72 publications

(87 citation statements)

References 33 publications

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“…This result is consistent with the increased motility of UOK262 cells, which has also been associated with epithelial to mesenchymal transition (EMT) ( Sciacovelli et al, 2016 ). Several GO terms related with mitochondrial processes, such as respiratory chain complexes, were down-regulated, consistently with the metabolic model predictions and previously observed decreased mitochondrial activity ( Sciacovelli et al, 2016 , Tyrakis et al 2017 ). We then assessed if changes in protein abundance of metabolic enzymes could be related with metabolic flux changes predicted by the model ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 89%

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Gonçalvès

Sciacovelli

Costa

et al. 2018

Metabolic Engineering

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Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.

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Section: Resultssupporting

confidence: 89%

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Gonçalvès

Sciacovelli

Costa

et al. 2018

Metabolic Engineering

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“…A study on kidney tumours showed that the excess of fumarate upregulates the proto‐oncogene Abelson murine leukemia viral oncogene homolog 1 (ABL1), which in turn stimulates: mammalian target of rapamycin (mTOR)/HIF‐1α signalling promoting aerobic glycolysis; nuclear localization of nuclear factor (erythroid‐derived 2)‐like 2 (NRF2); and ROS detoxification (Sourbier et al , ). Intriguingly, the metabolic phenotype of FH‐deficient cells could allow the tumour to resist unfavourable conditions affecting mitochondrial function, such as hypoxia (Tyrakis et al , ). Other studies have also shown that FH‐deficient cells and tissues exhibit defects in the urea cycle and arginine metabolism, highlighting an important extra‐mitochondrial metabolic role of cytosolic FH (Adam et al , ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

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“…Some of the selected mRNAs have been associated with the Krebs cycle or respiratory chain complexes. This is the case for Fahd1 (Pircher et al, 2015;Weiss et al, 2018), Lyrm5 (Floyd et al, 2016;Pagliarini et al, 2008), and Fh1 (Tyrakis et al, 2017). Interestingly, a reduction in Fh1 leads to mitochondrial respiratory chain defects, particularly in the complex I and II (Tyrakis et al, 2017).…”

Section: Transcript Analysis Reveals Oxidative Phosphorylation As a Cmentioning

confidence: 86%

“…This is the case for Fahd1 (Pircher et al, 2015;Weiss et al, 2018), Lyrm5 (Floyd et al, 2016;Pagliarini et al, 2008), and Fh1 (Tyrakis et al, 2017). Interestingly, a reduction in Fh1 leads to mitochondrial respiratory chain defects, particularly in the complex I and II (Tyrakis et al, 2017). Other validated mRNAs, such as Lonp1 or Atg13, have a mitochondrial protease function (Bota & Davies, 2016;Hoshino et al, 2014) or are linked to autophagy of the mitochondrion (Kaizuka & Mizushima, 2016), respectively.…”

Section: Transcript Analysis Reveals Oxidative Phosphorylation As a Cmentioning

confidence: 94%

Cardiomyocyte-specific Srsf3 deletion reveals a mitochondrial regulatory role

Dumont

Zhou

et al. 2020

Preprint

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AbstractSrsf3 was recently reported as being necessary to preserve RNA stability via an mTOR mechanism in a cardiac mouse model in adulthood. Here, we demonstrate the link between Srsf3 and mitochondrial integrity in an embryonic cardiomyocyte-specific Srsf3 conditional knockout (cKO) mouse model. Fifteen-day-old Srsf3 cKO mice showed dramatically reduced (below 50%) survival and reduced left ventricular systolic performance, and histological analysis of these hearts revealed a significant increase in cardiomyocyte size, confirming the severe remodelling induced by Srsf3 deletion. RNA-seq analysis of the hearts of 5-day-old Srsf3 cKO mice revealed early changes in expression levels and alternative splicing of several transcripts related to mitochondrial integrity and oxidative phosphorylation. Likewise, the levels of several protein complexes of the electron transport chain decreased, and mitochondrial complex I-driven respiration of permeabilized cardiac muscle fibres from the left ventricle was impaired. Furthermore, transmission electron microscopy analysis showed disordered mitochondrial length and cristae structure. Together with its indispensable role in the physiological maintenance of mouse hearts, these results highlight the previously unrecognized function of Srsf3 in regulating mitochondrial integrity.

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Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects

Cited by 72 publications

References 33 publications

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells

Oncometabolites in cancer aggressiveness and tumour repopulation

Cardiomyocyte-specific Srsf3 deletion reveals a mitochondrial regulatory role

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