Positive Contribution of Pathogenic Mutations in the Mitochondrial Genome to the Promotion of Cancer by Prevention from Apoptosis

Abstract

The role of mitochondrial dysfunction in cancer has been a subject of great interest and much ongoing investigation. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations contribute to the promotion of carcinomas remains unsolved. Here we used trans-mitochondrial hybrids (cybrids) containing a common HeLa nucleus and mtDNA of interest to compare the role of mtDNA against the common nuclear background. We constructed cybrids with or without a homoplasmic pathogenic point mutation at nucleotide position 8,993 or 9,176 in the mtDNA ATP synthase subunit 6 gene (MTATP6) derived from patients with mitochondrial encephalomyopathy. When the cybrids were transplanted into nude mice, the MTATP6 mutations conferred an advantage in the early stage of tumor growth. The mutant cybrids also increased faster than wild type in culture. To complement the mtDNA mutations, we transfected a wild-type nuclear version of MTATP, whose codons were converted to the universal genetic codes containing a mitochondrial target sequence, into the nucleus of cybrids carrying mutant MTATP6. The restoration of MTATP slowed down the growth of tumor in transplantation. Conversely, expression of a mutant nuclear version of MTATP6 in the wild-type cybrids declined respiration and accelerated the tumor growth. These findings showed that the advantage in tumor growth depended upon the MTATP6 function but was not due to secondary nuclear mutations caused by the mutant mitochondria. Because apoptosis occurred less frequently in the mutant versus wild-type cybrids in cultures and tumors, the pathogenic mtDNA mutations seem to promote tumors by preventing apoptosis. (Cancer Res 2005; 65(5): 1655-63)

Regulation of mitochondrial DNA content and cancer

“…Additionally, since the inheritance of mitochondrial haplotype U is associated with approximately 2 -fold increased risk of prostate cancer and 2.5-fold increased risk of renal cancer in white North America individuals (Booker et al, 2006), mtDNA definitely affects initiation of cancer. Growth advantage of the cancer cells with specific mutant mtDNA were also demonstrated in vivo mouse model system using cybrid (transmitochondrial hybrid) cells (Petros et al, 2005;Shidara et al, 2005), indicating that specific mutations of mtDNA give advantage of survival to cancer cells. However, Coller et al (Coller et al, 2001) showed that cancer progenitor cells already achieve homoplasmy through stochastic redistribution of the mitochondrial mutation and claimed that replicative advantage of point mutant mtDNA and selective expansion of cancer cells with specific mutant mtDNA are not always necessary to explain homoplasmy of mutant mtDNA in cancer.…”

Mitochondria as therapeutic targets for cancer chemotherapy

“…One connection is provided by hexokinase II, a glycolytic enzyme that may participate in the Warburg phenomenon and that also can interact with mitochondrial membranes to inhibit MOMP (Robey and Hay, 2005). Another link is given by pathogenic mutations in the mitochondrial genome that may reduce spontaneous apoptosis in cancer cell lines (Shidara et al, 2005).…”

Mitochondrial DNA repair in aging and disease

“…Mitochondrial DNA mutations in tumors also could be due to the effect of aging (93,94). Shidara et al showed that specific point mutations in mtDNA accelerate growth and reduce apoptosis in a variety of tumors, supporting the notion that some mtDNA mutations in tumors have functional advantages that promote tumor growth (121). Additionally, mitochondria are key players in tumor control by apoptosis.…”