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

Gonçalvès, Emanuel; Sciacovelli, Marco; Costa, Ana S.H.; Tran, Maxine; Johnson, Timothy Isaac; Machado, Daniel; Frezza, Christian; Sáez-Rodríguez, Julio

doi:10.1016/j.ymben.2017.11.011

Cited by 22 publications

(19 citation statements)

References 43 publications

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“…3). Gonçalves et al reported that pyruvate dehydrogenase activity was inhibited through its phosphorylation in UOK262 cells 10 , which is consistent with the results observed in this study (Fig. 3).…”

Section: Discussionsupporting

confidence: 93%

“…Via metabolome analysis, Adam et al and Zheng et al revealed that FH inactivation altered urea cycle metabolism and caused arginine auxotrophy 8 , 9 . In addition, Gonçalves et al demonstrated the increased phosphorylation of pyruvate dehydrogenase and restriction of carbon entry from glucose to the TCA cycle in FH-deficient cells by phosphoproteome analysis and 13 C tracer analysis 10 . As described above, how FH defect modulates cellular energy metabolism has been addressed by various approaches.…”

Section: Introductionmentioning

confidence: 99%

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Direct and quantitative analysis of altered metabolic flux distributions and cellular ATP production pathway in fumarate hydratase-diminished cells

Noguchi

Ishikawa

Wakita

et al. 2020

Sci Rep

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Fumarate hydratase (FH) is an enzyme in the tricarboxylic acid (TCA) cycle, biallelic loss-of-function mutations of which are associated with hereditary leiomyomatosis and renal cell cancer. However, how FH defect modulates intracellular metabolic fluxes in human cells has remained unclear. This study aimed to reveal metabolic flux alterations induced by reduced FH activity. We applied 13 c metabolic flux analysis (13 C-MFA) to an established cell line with diminished FH activity (FH dim) and parental HEK293 cells. FH dim cells showed reduced pyruvate import flux into mitochondria and subsequent TCA cycle fluxes. Interestingly, the diminished FH activity decreased FH flux only by about 20%, suggesting a very low need for FH to maintain the oxidative TCA cycle. Cellular ATP production from the TCA cycle was dominantly suppressed compared with that from glycolysis in FH dim cells. Consistently, FH dim cells exhibited higher glucose dependence for ATP production and higher resistance to an ATP synthase inhibitor. In summary, using FH dim cells we demonstrated that FH defect led to suppressed pyruvate import into mitochondria, followed by downregulated TCA cycle activity and altered ATP production pathway balance from the TCA cycle to glycolysis. We confirmed that 13 c-MFA can provide direct and quantitative information on metabolic alterations induced by FH defect. Fumarate hydratase (FH) is one of the enzymes in the tricarboxylic acid (TCA) cycle and catalyses the hydration of fumarate to malate. FH gene mutations causing loss of function are known to be associated with predispositions to hereditary leiomyomatosis and renal cell cancer (HLRCC) 1,2. This syndrome is characterised by cutaneous and uterine leiomyoma and an aggressive form of type 2 papillary renal carcinoma, which is often fatal 3. Since the TCA cycle plays an important role in cellular energy metabolism, FH defect leads to significant metabolic reprogramming. Effects of FH defect on cellular metabolism have been well studied using Fh1 (murine FH)-knockout mouse cells and FH-deficient UOK262 cells derived from HLRCC-associated kidney tumour 4. Yang et al., Frezza et al. and O'Flaherty et al. indirectly demonstrated the downregulated mitochondrial metabolism and the upregulated glycolysis in FH-inactivated cells by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) 5-7. Via metabolome analysis, Adam et al. and Zheng et al. revealed that FH inactivation altered urea cycle metabolism and caused arginine auxotrophy 8,9. In addition, Gonçalves et al. demonstrated the increased phosphorylation of pyruvate dehydrogenase and restriction of carbon entry from glucose to the TCA cycle in FH-deficient cells by phosphoproteome analysis and 13 C tracer analysis 10. As described above, how FH defect modulates cellular energy metabolism has been addressed by various approaches. However, to the best of our knowledge, a 13 C metabolic flux analysis (13 C-MFA)-based approach has not been applied to address the impact of FH defect on ...

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Direct and quantitative analysis of altered metabolic flux distributions and cellular ATP production pathway in fumarate hydratase-diminished cells

Noguchi

Ishikawa

Wakita

et al. 2020

Sci Rep

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“…First, as often observed in mitochondrial diseases, FH-deficient cells increase their glycolytic rates and instead of oxidising glucose in the mitochondria they shunt it into lactate production [34] and other glycolytic branches, including the pentose phosphate pathway (PPP) [35]. Interestingly, as will be detailed in section 3.2.2, this glycolytic shift is supported by a transcriptional reprogramming of glycolytic enzymes and the inhibition of pyruvate dehydrogenase (PDH), which in turn blocks the entry of glucose into the mitochondria [36] (Fig. 2 and Fig.…”

Section: Fh Loss Induces a Multi-layer Cellular Reprogramming That Leads To Transformation 31 Metabolic Rewiring In Fh-deficient Cellsmentioning

confidence: 99%

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Schmidt

Sciacovelli

Frezza

2020

Seminars in Cell & Developmental Biology

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103

102

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Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation, but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the step wise neoplastic progression after FH loss.

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“…In fact, since these networks are built based on genomic information they may contain false positive reactions (reactions which should not be included) and false negatives (missing reactions). Recon2 is a highly curated reconstruction for the human metabolic network applied in many studies, but improved versions are regularly released, such as Recon3D, which has been recently introduced but has still not been used in the field of metabolomics ( 59 – 62 ). The other challenge is the algorithm choice to extract sub-networks.…”

Section: Discussionmentioning

confidence: 99%

An Untargeted Metabolomics Approach to Investigate the Metabolic Modulations of HepG2 Cells Exposed to Low Doses of Bisphenol A and 17β-Estradiol

et al. 2018

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The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (1H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10−6M, 10−9M, and 10−12M), vs. the female reference hormone 17β-estradiol (E2, 10−9M, 10−12M, and 10−15M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.

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

Cited by 22 publications

References 43 publications

Direct and quantitative analysis of altered metabolic flux distributions and cellular ATP production pathway in fumarate hydratase-diminished cells

Direct and quantitative analysis of altered metabolic flux distributions and cellular ATP production pathway in fumarate hydratase-diminished cells

Fumarate hydratase in cancer: A multifaceted tumour suppressor

An Untargeted Metabolomics Approach to Investigate the Metabolic Modulations of HepG2 Cells Exposed to Low Doses of Bisphenol A and 17β-Estradiol

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