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Molecular and Cellular Biology, December 2004, p. 10933-10940, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10933-10940.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

José I. Piruat,1 C. Oscar Pintado,2 Patricia Ortega-Sáenz,1 Marta Roche,1 and José López-Barneo1*

Laboratorio de Investigaciones Biomédicas, Hospital Universitario Virgen del Rocío,1 Centro de Producción y Experimentación Animal, Universidad de Sevilla, Seville, Spain2

Received 19 July 2004/ Returned for modification 3 September 2004/ Accepted 23 September 2004

The SDHD gene encodes one of the two membrane-anchoring proteins of the succinate dehydrogenase (complex II) of the mitochondrial electron transport chain. This gene has recently been proposed to be involved in oxygen sensing because mutations that cause loss of its function produce hereditary familiar paraganglioma, a tumor of the carotid body (CB), the main arterial chemoreceptor that senses oxygen levels in the blood. Here, we report the generation of a SDHD knockout mouse, which to our knowledge is the first mammalian model lacking a protein of the electron transport chain. Homozygous SDHD–/– animals die at early embryonic stages. Heterozygous SDHD+/– mice show a general, noncompensated deficiency of succinate dehydrogenase activity without alterations in body weight or major physiological dysfunction. The responsiveness to hypoxia of CBs from SDHD+/– mice remains intact, although the loss of an SDHD allele results in abnormal enhancement of resting CB activity due to a decrease of K+ conductance and persistent Ca2+ influx into glomus cells. This CB overactivity is linked to a subtle glomus cell hypertrophy and hyperplasia. These observations indicate that constitutive activation of SDHD+/– glomus cells precedes CB tumor transformation. They also suggest that, contrary to previous beliefs, mitochondrial complex II is not directly involved in CB oxygen sensing.

* Corresponding author. Mailing address: Laboratorio de Investigaciones Biomédicas, Edificio de Laboratorios, 2a Planta, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013, Seville, Spain. Phone: (34)-954-617090 or (34)-955-012648. Fax: (34)-954-617301. E-mail: jose.l.barneo.sspa{at}juntadeandalucia.es.

Molecular and Cellular Biology, December 2004, p. 10933-10940, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10933-10940.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lopez-Barneo, J., Ortega-Saenz, P., Pardal, R., Pascual, A., Piruat, J. I. (2008). Carotid body oxygen sensing. Eur Respir J 32: 1386-1398 [Abstract] [Full Text]  
  • Baysal, B E (2008). Clinical and molecular progress in hereditary paraganglioma. J. Med. Genet. 45: 689-694 [Abstract] [Full Text]  
  • Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S., Schumacker, P. T. (2008). Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis. Mol. Cell. Biol. 28: 718-731 [Abstract] [Full Text]  
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