Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction.
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.
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
Blanca
B
Díaz-Castro
C Oscar
CO
Pintado
Paula
P
García-Flores
José
J
López-Barneo
José I
JI
Piruat
D000255:Adenosine Triphosphate / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D016923:Cell Death; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D013385:Succinate Dehydrogenase
D002395:Catecholamines; D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; C574938:SDHD protein, mouse; D013385:Succinate Dehydrogenase; D010100:Oxygen