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Article

Differential Impairment of Catecholaminergic Cell Maturation and Survival by Genetic Mitochondrial Complex II Dysfunction

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Pages 3347-3357 | Received 27 Jan 2012, Accepted 10 Jun 2012, Published online: 20 Mar 2023
 

Abstract

The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a “floxed” SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson's disease. Unexpectedly, TH+ neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period.

ACKNOWLEDGMENTS

Support was obtained from the Marcelino Botín Foundation, the Spanish Ministries of Science and Health (TERCEL), and the Andalusian Government.

We thank José Antonio Rodríguez-Gómez, María Hidalgo-Figueroa, and Alberto Castejón for technical assistance. Confocal analyses were performed with software provided by Konstantin Levitsky (Optical Microscopy and Confocal Unit of IBiS; patent no. P201100749).

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