Neurochemical Research

, Volume 41, Issue 4, pp 696–706 | Cite as

Loss of SDHB Elevates Catecholamine Synthesis and Secretion Depending on ROS Production and HIF Stabilization

  • Yuria Saito
  • Kiyo-aki Ishii
  • Yuichi Aita
  • Tatsuhiko Ikeda
  • Yasushi Kawakami
  • Hitoshi Shimano
  • Hisato Hara
  • Kazuhiro Takekoshi
Original Paper


Germline mutations in genes encoding succinate dehydrogenase subunits are associated with the development of familial pheochromocytomas and paragangliomas [hereditary paraganglioma/pheochromocytoma syndrome (HPPS)]. In particular, a mutation in succinate dehydrogenase subunit B (SDHB) is highly associated with abdominal paraganglioma and subsequent distant metastasis (malignant paraganglioma), indicating the importance of SDHB genetic testing. The discovery of HPPS suggests an association among genetic mitochondrial defects, tumor development, and catecholamine oversecretion. To investigate this association, we transfected pheochromocytoma cells (PC12) with SDHB-specific siRNA. SDHB silencing virtually abolished complex II activity, demonstrating the utility of this in vitro model for investigating the pseudo-hypoxic drive hypothesis. Lack of complex II activity resulting from RNA interference of SDHB increased tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion. Reduced apoptosis was observed accompanied by Bcl-2 accumulation in PC12 cells, consistent with the phenotypes of paragangliomas with SDHB mutations. In addition, SDHB silencing increased reactive oxygen species (ROS) production and nuclear HIF1α stabilization under normoxic conditions. Furthermore, phenotypes induced by complex II activity knockdown were abolished by pretreatment with N-acetyl cysteine (an ROS scavenger) and by prior HIF1α knockdown, indicating an ROS- and HIF1α-dependent mechanism. Our results indicate that increased ROS may act as signal transduction messengers that induce HIF1α stabilization and may be necessary for the pseudo-hypoxic states observed in our experimental model. To our knowledge, this is the first study demonstrating that pseudo-hypoxic states resulting from SDHB knockdown are associated with increased TH activity and catecholamine oversecretion.


Succinate dehydrogenase Hereditary paraganglioma/pheochromocytoma syndrome Catecholamine Reactive oxygen species 



This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, No. 21591168 (to K.T.) and No. 23591889 (to H.H).

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflicts of interest, financial or otherwise.

Supplementary material

11064_2015_1738_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 12 kb)
11064_2015_1738_MOESM2_ESM.pdf (110 kb)
Supplementary material 2 (PDF 110 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yuria Saito
    • 1
  • Kiyo-aki Ishii
    • 4
  • Yuichi Aita
    • 1
  • Tatsuhiko Ikeda
    • 3
  • Yasushi Kawakami
    • 1
  • Hitoshi Shimano
    • 2
  • Hisato Hara
    • 3
  • Kazuhiro Takekoshi
    • 5
  1. 1.Department of Molecular Laboratory Medicine, Faculty of MedicineUniversity of TsukubaIbarakiJapan
  2. 2.Department of Internal Medicine (Endocrinology and Metabolism), Faculty of MedicineUniversity of TsukubaIbarakiJapan
  3. 3.Department of Breast-Thyroid-Endocrine Surgery, Faculty of MedicineUniversity of TsukubaIbarakiJapan
  4. 4.Department of Disease Control and HomeostasisKanazawa University Graduate School of Medical ScienceKanazawaJapan
  5. 5.Division of Sports Science, Faculty of MedicineUniversity of TsukubaIbarakiJapan

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