[Frontiers in Bioscience E3, 194-200, January 1, 2011]

[Frontiers in Bioscience E3, 194-200, January 1, 2011]

Alterations of respiratory chain complexes in sporadic pheochromocytoma

Rene G. Feichtinger¹, Franz A. Zimmermann¹, Johannes A. Mayr¹, Daniel Neureiter², Manfred Ratschek³, Neil Jones¹, Wolfgang Sperl¹, Barbara Kofler¹

1Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Muellner Hauptstr. 48, A-5020 Salzburg, Austria, ²Department of Pathology, University Hospital Salzburg, Paracelsus Medical University, Muellner Hauptstr. 48, A-5020 Salzburg, Austria, ³Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Material and methods: 3.1. Ethics; 3.2. Samples; 3.3. Spectrophotometric detection of OXPHOS enzyme activities; 3.4. Western blot analysis; 3.5. Immunohistochemical staining and analysis; 3.6. Determination of mitochondrial DNA copy number
4. Results
5. Discussion
6. Acknowledgements
7. References

1. ABSTRACT

Succinate dehydrogenase (SDH) has been associated with carcinogenesis in hereditary pheochromocytoma (PC) and paraganglioma. We investigated if a similar association applies to sporadic pheochromocytoma. No genetic alteration was found in the SDHB, SDHC or SDHD genes of sporadic PC. However, in eight of nine sporadic PCs the SDH activity was, on average, reduced by 40%; moreover, the activities of the other oxidative phosphorylation (OXPHOS) complexes and citrate synthase were significantly lower compared to normal kidney tissue. Furthermore, immunohistochemical staining revealed a significant down-regulation of respiratory chain complexes. Since no pathogenic mutations were detected in the von Hippel-Lindau (VHL) gene, we can rule out that VHL deficiency is causing the general reduction of OXPHOS enzymes observed in the PCs investigated. In contrast to the single enzyme defects found in a subset hereditary PCs, a more generalized reduction of mitochondrial respiration seems to be present in most sporadic PCs. Strikingly, one of the nine PCs showed specific loss of complex I and a compensatory up-regulation of complexes II-V, which is a phenotype usually characteristic of oncocytic tumors.