[CANCER RESEARCH 64, 7640 –7644, October 15, 2004] Meeting Report Highlights of the National Cancer Institute Workshop on Mitochondrial Function and Cancer Mary Ellen Perry, 1 Chi V. Dang, 2 David Hockenbery, 3 and Ute Moll 4 1 Division of Cancer Biology, National Cancer Institute, NIH, Bethesda, Maryland; 2 Johns Hopkins University School of Medicine, Baltimore, Maryland; 3 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington; and 4 Department of Pathology, Stony Brook University, Stony Brook, New York Introduction This workshop was stimulated by the desire of the National Cancer Institute to examine various aspects of mitochondrial function as they relate to tumorigenesis, apoptosis, and cancer therapy. Through en- dosymbiosis, a bacterial ancestor took its position in the eukaryotic cytoplasm and serves as the cellular powerhouse. It has become increasingly clear, however, that not only do mitochondria produce ATP through the coupling of electron transport with proton pumping, they are also at the crossroads of many other metabolic activities, including heme biosynthesis, single carbon metabolism, and fatty acid metabolism. In addition to serving as central stations for many met- abolic functions, mitochondria integrate stress signals to trigger pro- grammed cell death or apoptosis. Aging and tumorigenesis are both associated with mitochondrial DNA mutations, although how these mutations impact mitochondrial function and whether they are a cause or a consequence of aging remains to be established. Although it is known that tumor hypoxia elicits an adaptive transcriptional response, how mitochondrial function changes in tumorigenesis and whether mitochondrial defects contribute to the Warburg effect (a universal high acidity in tumor tissues compared with the surrounding normal tissue; described in 1928 by Otto Warburg) remain controversial. The topics covered by this workshop have been selected to shed some light on these intriguing, yet not fully understood areas of mitochondrial function. Mitochondrial DNA Mutations and Cancer The workshop was opened by Kornelia Polyak (Dana-Farber Can- cer Institute) who gave a presentation of her seminal work on somatic mutations in the mitochondrial genome of colorectal cancer cells. Polyak showed that mutations in mitochondrial DNA occur somati- cally and are present in the majority of human tumors. The cancer cells are “homoplasmic” for the mutation, meaning that all copies of the mitochondrial DNA contain the mutations. The mechanism by which the mitochondria become homoplasmic is not known, but may involve a replicative advantage on the part of the mitochondrial genome, on the mitochondria or on the cell. Polyak generated cells that differed solely in their mitochondrial DNA and demonstrated that mitochondrial DNA, in combination with nuclear factors, may influ- ence the ability of cells to undergo p53-mediated apoptosis in re- sponse to stress, suggesting the mitochondrial genome may contribute causally to cancer. However, proof of this important concept remains elusive. The high copy number and homoplasmy of mitochondria make them useful markers for detecting cancer from fine needle aspirates or paraffin sections (David Sidransky, Johns Hopkins School of Medi- cine). Squamous cell carcinoma of the head and neck is a devastating disease that often recurs after surgical resection. Sidransky showed that somatic mitochondrial mutations in head and neck cancers occur before dysplasia and can be used to detect early recurrences. In one patient, the same mitochondrial mutation was found in recurrences that arose over many years, indicating that mitochondria may be markers of clonal expansion. Furthermore, because of the homoplas- mic nature and increased copy number of the mitochondrial genome, mutations in mitochondrial DNA were more readily detectable in dilute clinical samples than were mutations in single copy nuclear genes such as p53. The tumor-associated mitochondrial DNA mutations are most likely initiated as polymerase errors or as a consequence of DNA damage by endogenous or exogenous agents. The ability of mitochon- dria to deal with DNA damage is limited, because the organelle lacks a full complement of the enzymes required for mismatch repair, nucleotide excision repair and recombinational repair (Daniel Bogen- hagen, Stony Brook University). The incidence of mitochondrial mutations may be influenced by mitochondrial DNA binding proteins that either protect the DNA from damage or block the genome from DNA repair enzymes. Mitochondrial DNA must be highly packaged to fit into the organelle, but it is not packaged into nucleosomes. To begin to understand how mitochondrial DNA is packaged, Bogenha- gen identified proteins that bind to mitochondrial DNA. One of these proteins, TFAM, acts as a transcriptional activator at low ratios of protein to DNA but actually inhibits transcription at high ratios. This same protein inhibits base excision repair at high ratios of protein to DNA, suggesting that the mitochondrial proteome may influence the incidence of mitochondrial DNA mutations. Role of Mitochondria in Apoptosis Douglas R. Green (La Jolla Institute for Allergy and Immunology) reported that among the earliest targets of the executioner caspases are the permeabilized mitochondria themselves. In the absence of caspase activation, cytochrome c can sustain electron transport and ATP generation in the permeabilized mitochondria. Once caspases are activated, electron transport is disrupted. Examination of caspase-3 substrates within the mitochondria permitted the identification of a key substrate, p75, a component of the large complex I of the electron transport chain, which is cleaved at a single site by caspase 3. Green showed that p75 cleavage by caspases disrupts mitochondrial integrity and leads to loss of electron transport, loss of m, generation of reactive oxygen species, and a rapid decline in ATP levels in the cell, thus preventing a recovery of m. However, p75 cleavage has no effect on cytochrome c release. p75 cleavage also accelerates phos- phatidylserine externalization and loss of plasma membrane integrity without affecting other aspects of caspase-dependent apoptosis such as DNA fragmentation. Therefore, the rapid action of activated Received 6/4/04; revised 8/16/04; accepted 8/19/04. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: The workshop was held on February 22–24, 2004 in Bethesda, Maryland. Requests for reprints: Mary Ellen Perry, Cancer Cell Biology Branch, Division of Cancer Biology, National Cancer Institute, Room 5034, 6130 Executive Blvd., Rockville, MD 20852; E-mail: perryma@mail.nih.gov. ©2004 American Association for Cancer Research. 7640 Research. on November 27, 2021. © 2004 American Association for Cancer cancerres.aacrjournals.org Downloaded from