ECE2013 Poster Presentations Endocrine tumours and neoplasia (66 abstracts)
Mitochondrial ultrastructure in pseudohypoxic succinate dehydrogenase B and von Hippel–Lindau gene mutation derived pheochromocytomas and paragangliomas
Maria Tsokos 1 , Stephanie Fliedner 2, , Tamara Prodanov 2 , Mones Abu-Asab 1, , Jailan Osman 1 , Hendrik Lehnert 3 & Karel Pacak 2
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 2Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; 31st Department of Medicine, University Hospital Scheswig-Holstein Campus Lübeck, Lübeck, Germany; 4Section of Immunopathology, National Eye Institute, National Institutes of Health, Bethedsa, Maryland, USA.
Mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D have been shown to hamper oxidative phosphorylation and predispose to pheochromocytomas (PHEOs) and paragangliomas (PGLs). These tumors are characterized by a glycolytic and pseudohypoxic phenotype, which is also seen in most PHEOs/PGLs occurring as part of von Hippel–Lindau (VHL) syndrome, due to VHL gene mutations. The rate of extra-adrenal tumor origin and malignancy however is particularly high in SDHB-PHEOs/PGLs, while VHL-PHEOs/PGLs are almost always adrenal and benign.
We have recently shown that despite decreased complex II activity, mRNA and protein abundance of several oxidative phosphorylation subunits is elevated in SDHB compared to VHL PHEOs/PGLs.
Here we present ultrastructural evidence for vast differences in number and appearance of mitochondria in SDHB and VHL derived PHEOs/PGLs, as we have previously presented on a smaller patient cohort. Forty-three tissue samples of SDHB (47% metastatic) and VHL patients (0% metastatic) have been evaluated. In SDHB PHEOs/PGLs density and size of mitochondria was increased compared to VHL PHEOs/PGLs with a disrupted cristae structure in both types of PHEOs/PGLs. Western blot for the mitochondrial marker cytochrome C revealed higher levels in SDHB PHEOs/PGLs. No difference was observed between metastatic and non-metastatic SDHB tumors.
Our data indicates that disruption of the respiratory chain caused by SDHB mutations may lead to an accumulation of abnormal, possibly dysfunctional mitochondria. Further studies on live cells are mandated to conclude if the disrupted appearance of the mitochondria leads to a loss of mitochondrial membrane potential and functionality or reactive oxygen species generation and the potential role of aberrant mitochondria in metastatic potential.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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