Highlights of the National Cancer Institute Workshop on mitochondrial function and cancer

Abstract

The workshop illuminated several ways in which mitochondria are involved in cancer. The mitochondrial genome has become a useful source of markers for early detection of cancers. In addition, mutations in the mitochondrial genome may contribute to the development of cancer. The development of methods to engineer cells with homoplasmic, targeted mutations in their mitochondria would be a major advance toward answering this question. The mitochondrial proteome is also altered in cancer cells. Some of these alterations affect both mitochondrial bioenergetics and apoptosis regulation through dual function proteins, suggesting that these two processes are linked. Examples of such dual function proteins are cytochrome c, AIF, and HKII. We heard how extensively mitochondria communicate with other cellular compartments, influencing both transcription (through ROS and HIF1) and translation (through cardiolipin). In turn, the nuclear functions of Myc and HIF1 influence mitochondrial function. The mitochondria also exchange proteins with other organelles. For example, TR3 and p53 travel to the mitochondrial surface to stimulate apoptosis. In turn, AIF and cytochrome c are released from the mitochondria to exert their apoptogenic effects. It will be important to elucidate the regulatory mechanisms mediating transport of these proteins to various subcellular compartments and to decipher the specific function of each protein in each compartment. Both tumor suppressors and oncoproteins use and influence mitochondrial functions. The p53 tumor suppressor induces apoptosis, at least in part, by binding to the mitochondrial surface and activating Bax and Bak. ROS, thought to be generated from the mitochondria, plays a direct role in growth factor signaling. The Akt survival factor interacts with the bioenergetic protein HKII to prevent apoptosis. In addition, Akt can stimulate aerobic glycolysis without influencing mitochondrial oxidative phosphorylation, providing cells a survival advantage in conditions of nutrient deprivation. HIF1, which promotes angiogenesis, regulates expression of a number of mitochondrial proteins that may be involved in the adaptive response to hypoxia. Moreover, the c-Myc proto-oncoprotein induces expression of several mitochondrial proteins, some of which are involved in energy metabolism. The workshop participants enumerated a number of outstanding questions, including some very basic ones about mitochondrial biology. How are mitochondria replicated? How is their number controlled? How is homoplasmy obtained? Some more physiologic questions remain as well. How are energy metabolism and apoptosis linked? Is oxidative phosphorylation altered in cancer cells, or only glycolysis? What regulatory mechanisms control the switch to aerobic metabolism that is so characteristic of cancer cells? Can we target aerobic glycolysis to selectively kill tumor cells? Although we await the answers to these questions, the mitochondria are already providing us with diagnostic markers and treatment strategies for cancer.