Low aerobic mitochondrial energy metabolism in poorly- or undifferentiated neuroblastoma

Abstract

Background: Succinate dehydrogenase (SDH) has been associated with carcinogenesis in pheochromocytoma and paraganglioma. In the present study we investigated components of the oxidative phosphorylation system in human neuroblastoma tissue samples.

Methods: Spectrophotometric measurements, immunohistochemical analysis and Western blot analysis were used to characterize the aerobic mitochondrial energy metabolism in neuroblastomas (NB).

Results: Compared to mitochondrial citrate synthase, SDH activity was severely reduced in NB (n = 14) versus kidney tissue. However no pathogenic mutations could be identified in any of the four subunits of SDH. Furthermore, no genetic alterations could be identified in the two novel SDH assembly factors SDHAF1 and SDH5. Alterations in genes encoding nfs-1, frataxin and isd-11 that could lead to a diminished SDH activity have not been detected in NB.

Conclusion: Because downregulation of other complexes of the oxidative phosphorylation system was also observed, a more generalized reduction of mitochondrial respiration seems to be present in neuroblastoma in contrast to the single enzyme defect found in hereditary pheochromocytomas.

Figure 1

Activity of OXPHOS complexes in normal kidney tissues and NBs. a: citrate synthase (CS), b: complex I (CI), c: complex II (CII), d: complex III (CIII), e: complex IV (CIV), f: complex V (CV), g: mtDNA copy number.

Figure 2

Immunohistochemical staining of porin, complex II and complex III of NB, adjacent adrenal cortex and adrenal medulla. Immunohistochemical staining of porin (a, d, g), complex II subunit 70 kDa Fp (b, e, h) and complex III subunit Core2 (c, f, i) in unaffected adrenal tissue (a, b, c) and unaffected adrenal medulla (d, e, f) was compared to the adjacent NB tumor tissue (g, h, i). Magnification: Figure 2a - c 200×, Figure 2d - i 400×.

Figure 3

Western blot analysis of NBs and kidney tissue samples. Complex II (SDHA; subunit 70 kDa Fp), Complex III (subunit Core 2), GAPDH, VHL. Lane K: normal kidney cortex tissue, lanes 1-14 NB samples.