Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma

Rao, Jyotsna U.; Engelke, Udo F. H.; Rodenburg, Richard J.; Wevers, Ron A.; Pacák, Karel; Eisenhofer, Graeme; Qin, Nan; Küsters, Benno; Goudswaard, Angelina G.; Lenders, Jacques W.M.; Hermus, A.R.M.M.; Mensenkamp, Arjen R.; Kunst, Henricus P. M.; Sweep, Fred C.G.J.; Timmers, Henri J L M

doi:10.1158/1078-0432.ccr-12-3922

Cited by 53 publications

(64 citation statements)

References 37 publications

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“…In line with these results, we also found a decreased CO 2 production, suggesting a reduced glucose decarboxylation and an increased HIF1α expression in two clones. These results are in agreement with a recent study in which the authors demonstrated the presence of differences in determinants of energy metabolism in PGLs [31]. In particular, the authors reported that in all SDH-mutated tumours, they found an accumulation of succinate associated with a very low content of ATP/ADP/AMP.…”

Section: Discussionsupporting

confidence: 92%

Succinate Dehydrogenase Subunit B Mutations Modify Human Neuroblastoma Cell Metabolism and Proliferation

Rapizzi¹,

Ercolino²,

Fucci³

et al. 2014

HORM CANC

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Paragangliomas (PGLs) are rare neuroendocrine tumours. About 30-40 % of these tumours are mutated in one of the different susceptibility genes, including those encoding the different subunits of the succinate dehydrogenase, a complex involved both in the tricarboxylic acid cycle and in the oxygen transport chain. The aim of this work was to investigate whether SDHB mutations may account for alterations in cell metabolism and functions. Since human PGL cell lines are not available, we used the neuroblastoma cell line (SK-N-AS) stably transfected with the wild-type human SDHB or different SDHB-mutated constructs carrying some significant mutations found in our patients affected by PGLs. Similarly to succinate dehydrogenase (SDH)-mutated tumour cells, mutated SK-N-AS clones showed reduced SDH enzyme activity. All clones showed normal citrate synthase activity, reduced oxygen consumption and reduced carbonic anhydride production, thus demonstrating a decreased in mitochondrial metabolism. In two of the three mutated SK-N-AS, we also found an increase in HIF1α expression. Surprisingly and unexpectedly, in all the SDHB-mutated clones, we found a significant decrease in glucose uptake and in lactate culture medium concentration, suggesting also a decrease of cytosolic metabolism. Finally, we found that these energetic changes were associated to an increase in cell proliferation and migration. Overall, these data demonstrate that although SDHB mutations significantly downregulate both mitochondrial and cytoplasmic cellular metabolism, these mutations are associated to an upregulation of some cellular functions, such as growth rate and invasiveness.

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Section: Discussionsupporting

confidence: 92%

Succinate Dehydrogenase Subunit B Mutations Modify Human Neuroblastoma Cell Metabolism and Proliferation

Rapizzi¹,

Ercolino²,

Fucci³

et al. 2014

HORM CANC

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“…Interestingly, in an Sdhb À/À mouse tumor model, this succinate peak is correlated with the concentrations of succinate measured in the resected tumors by GC-MS. Demonstration of SDH inactivation is currently based on in vitro analyses of tissue samples: immunohistochemical analyses of SDHB, SDHA, and SDHD expression in FFPE tissues (16,18,22), direct succinate measurements on frozen tumor samples by nuclear magnetic resonance (NMR) spectroscopy (15,19,20,23), GC-MS, or liquid chromatography mass spectroscopy (LC-MS; refs. 13,17,21).…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers could serve as surrogate markers in the assessment of tumor response to specific treatments. Until now, no in vivo method to assess the functional consequences of SDHx mutations was available, and all existing tests were performed on surgical resected specimens (15)(16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

“…Succinate concentrations in the millimolar range-4 to 500 micromoles per gram depending on studies and procedureshave been reported in SDHx-mutated PPGL tumors, an increase of up to 100-fold compared with non-SDHx-mutated PPGL tumors (19,21,23). We hypothesized that these succinate levels could be detected noninvasively by in vivo proton magnetic resonance spectroscopy ( 1 H-MRS) in SDHx-mutated tumors, without the need for tissue sampling, similarly to 2-hydroxyglutarate in patients with IDH1/2-mutated gliomas (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Lussey-Lepoutre

Bellucci

Morin

et al. 2016

Clinical Cancer Research

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International audiencePurpose: Germline mutations in genes encoding mitochon-drial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1 H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb À/À or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n ¼ 5) or not (n ¼ 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1 H-MRS in all Sdhb À/À-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1 H-MRS results led to the identification of an unsus-pected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1 H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This non-invasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. Ó2015 AACR

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“…A few applications of HRMAS NMR spectroscopy to pediatric neuroblastomas have been described in the literature (Peet et al 2007, Wilson et al 2009, Imperiale et al 2011). More recently, Timmers' team has reported an in vitro 1 H-NMR spectroscopic study exploring the genotype-specific abnormalities in mitochondrial function associated with distinct profiles of energy metabolism and catecholamine content in PCCs and paragangliomas (Rao et al 2013). To date, to the best of our knowledge, no other HRMAS NMR investigations concerning healthy adrenal tissue and the related pathologies have been reported, particularly regarding the adrenal cortex.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic profile of the adrenal gland: from physiology to pathological conditions

Impériale¹,

Elbayed²,

Moussallieh³

et al. 2013

Endocrine-Related Cancer

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In this study, we i) assessed the metabolic profile of the normal adrenal cortex and medulla of adult human subjects by means of 1 H-high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy; ii) compared the biochemical profile of adenoma (Ad), adrenal cortical carcinoma (ACC), and pheochromocytoma (PCC) samples with that of healthy adrenal tissue samples; and iii) investigated the metabolic differences between ACCs and Ads as well as between ACCs and PCCs. Sixty-six tissue samples (13 adrenal cortical tissue, eight medullary tissue, 13 Ad, 12 ACC, and 20 PCC samples) were analyzed. Adrenaline and noradrenaline were undetectable in cortical samples representing the metabolic signature of the tissue derived from neural crest. Similarity between the metabolic profile of Ads and that of the normal adrenal cortex was shown. Inversely, ACC samples clearly made up a detached group exhibiting the typical stigmata of neoplastic tissue such as choline-containing compounds, biochemical markers of anaerobic processes, and increased glycolysis. Significantly higher levels of lactate, acetate, and total choline-containing compounds played a major role in the differentiation of ACCs from Ads. Moreover, the high fatty acid content of ACCs contributed to the cluster identification of ACCs. Of the 14 sporadic PCC samples, 12 exhibited predominant or exclusive noradrenaline secretion. The noradrenaline: adrenaline ratio was inverted in the normal medullary tissue samples. Multiple endocrine neoplasia type 2-and NF1-related PCC samples exhibited both adrenaline and noradrenaline secretion. In the von Hippel-Lindau disease-related PCC samples, only noradrenaline secretion was detected by HRMAS NMR spectroscopy. This study is one of the first applications of metabolomics to adrenal pathophysiology and it is the largest study to report HRMAS NMR data related to the adrenal cortex and adrenal cortical tumors.

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Genotype-Specific Abnormalities in Mitochondrial Function Associate with Distinct Profiles of Energy Metabolism and Catecholamine Content in Pheochromocytoma and Paraganglioma

Cited by 53 publications

References 37 publications

Succinate Dehydrogenase Subunit B Mutations Modify Human Neuroblastoma Cell Metabolism and Proliferation

Succinate Dehydrogenase Subunit B Mutations Modify Human Neuroblastoma Cell Metabolism and Proliferation

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Metabolomic profile of the adrenal gland: from physiology to pathological conditions

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