Few reports support the idea that decreasing respiratory chain activity promotes tumor growth in cancer cells. For example, enhancement of complex I activity through NADH dehydrogenase expression strongly interferes with tumor growth and metastasis, while inhibition of complex I CYT387 supply enhances the metastatic potential of already aggressive breast cancer cells. Oncogene activity can decrease mitochondrial complex I activity, supporting a malignant phenotype. A variety of human tumors display reduced SIRT3 expression, supporting the hypothesis that sirtuin 3 acts as a tumor suppressor in humans ; because the deacetylase enzyme SIRT3 targets enzymes that are involved in multiple mitochondrial oxidative pathways, with the cumulative effect of promoting nutrient oxidation and energy production, its anti-oncogenic activity may reside in enhancing oxidative metabolism to the CHIR-99021 clinical trial detriment of the efflux of TCA cycle metabolites for anabolic purposes. Based on these considerations, the VDR may be regarded as a mitochondriatargeting tumor facilitator, similar to the role proposed for the leptin receptor, the signaling of which supports cancer cell metabolism by suppressing mitochondrial respiration. In our experimental model, we were unable to discriminate between direct or indirect nuclear-triggered control of mitochondrial transcription by the VDR. Our observation that both nuclear- and mitochondrially encoded COX transcripts are modulated by VDR activity may be explained by concerted mitochondrial and nuclear transcriptional control that is exerted by the VDR, although we cannot exclude the possibility of nuclear signaling by the receptor, followed by cross-talk with the mitochondrial transcription machinery. However, given the abundant presence of the VDR in the mitochondrial compartment and its similar action to that reported for other steroid receptors docking at responsive elements on mtDNA, one may hypothesize that direct binding of the receptor to mtDNA occurs. Our in silico analysis of VDRE sites on the mitochondrial genome has provided strong indications of direct transcriptional control that is exerted by the VDR on mtDNA. Further studies will demonstrate the accuracy of this prediction. The binding and transcriptional control remains to be demonstrated experimentally in future investigations. In our opinion, it is reasonable to conclude that nuclear and mitochondrial VDR signaling are integrated, as described for the glucocorticoid receptor, and that further studies will demonstrate both direct and indirect modalities of VDR action on mitochondrial transcription.