Induction of ANT2 gene expression in liver of patients with mitochondrial DNA depletion.

We have previously described two cases of children with a liver mitochondrial DNA (mtDNA) depletion syndrome, characterised by a low ratio of mtDNA to nuclear DNA. Light microscopy performed on liver biopsy showed abnormal hepatocytes with a characteristic 'oncocytic' appearance, indicative of perturbed oxidative phosphorylation. The adenine nucleotide translocator (ANT), the last step in oxidative phosphorylation catalyses the exchange of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) between the cytosol and mitochondria. The ANT2 gene, which is not normally expressed in human tissues, encodes an isoform preferentially expressed under conditions of glycolytic metabolism. ANT2 gene expression is regulated by a transcription factor involved in a molecular mechanism selecting for the import of glycolytic ATP into the mitochondrial matrix. This ATP import is required in highly proliferative cells, such as tumour cells, which are highly dependent on glycolysis for ATP synthesis. We postulated that, as a result of the defective oxidative phosphorylation observed in these patient biopsies, the ANT2 expression would be induced. We simultaneously quantified the mtDNA depletion and the ANT2 gene expression in liver biopsies from the two patients and six controls. ANT2 mRNA levels were significantly increased in the two patient liver biopsies. Moreover, in one patient, the liver mtDNA depletion was found to be partially reversed after less than 4 years and this reversion was coupled to a concomitant decrease of the ANT2 expression. These results suggest that dysfunction of oxidative phosphorylation could lead to a switch from mitochondrial to glycolytic ATP production, to restore tissue-specific energy requirements.

No evidence of thyrotropin receptor and G(s alpha) gene mutation in high iodine uptake thyroid carcinoma.

Usually, thyroid carcinoma presents as a cold nodule on radioiodine scintigraphy. High-uptake nodules on iodine thyroid scans are associated with an exceedingly low incidence of malignancy. Only 29 cases of carcinomas appearing as hot or warm nodules have as yet been reported. From 1993 to 1999, we have observed eight similar cases (4 hot and 4 warm thyroid nodules) suggesting that thyroid carcinomas may not be as rare as usually considered in these circumstances. Four tumors were available for molecular analysis on paraffin-embedded sections. Because no mutations were found in the whole coding portions of thyrotropin-receptor (TSH-R) gene and fragments encompassing the mutational hot spots of the G(s alpha) gene, it is unlikely that activating mutations of the TSH-R or G(s alpha) genes were involved in these carcinomas.