Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas.</p> <p>Methods</p> <p>We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (<it>MT-ATP6, MT-CO1, MT-CYB, MT-ND1</it>, <it>MT-ND6</it>, and <it>MT-RNR1</it>) were quantified in 62 cancer tissues by real-time RT-PCR.</p> <p>Results</p> <p>Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene <it>RNR1 </it>might be used as a predictor of tumour sensitivity to chemotherapy.</p> <p>Conclusion</p> <p>In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.</p

Thyroid hormone action: The p43 mitochondrial pathway. Methods

The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial _pathway is now well established. The demonstration that TR.al mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into ttùtochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones. The use of a T3 photo affinity label derivative (T3-PAL) allowed detectiug two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRal, mitochondrial T3 receptors were identified as truncated T.Ral forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that p43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. Invitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, andtransformation. Generation of transgenic mice demonstrated the involve1nent of this mitochondrial pathwayin the determination of muscle phenotype, glucose metabolism, and thermogenesis