Skip to main content
Article thumbnail
Location of Repository

Mitochondrial DNA Instability and Metabolic Shift in Human Cancers

By Hsin-Chen Lee and Yau-Huei Wei

Abstract

A shift in glucose metabolism from oxidative phosphorylation to glycolysis is one of the biochemical hallmarks of tumor cells. Mitochondrial defects have been proposed to play an important role in the initiation and/or progression of various types of cancer. In the past decade, a wide spectrum of mutations and depletion of mtDNA have been identified in human cancers. Moreover, it has been demonstrated that activation of oncogenes or mutation of tumor suppressor genes, such as p53, can lead to the upregulation of glycolytic enzymes or inhibition of the biogenesis or assembly of respiratory enzyme complexes such as cytochrome c oxidase. These findings may explain, at least in part, the well documented phenomena of elevated glucose uptake and mitochondrial defects in cancers. In this article, we review the somatic mtDNA alterations with clinicopathological correlations in human cancers, and their potential roles in tumorigenesis, cancer progression, and metastasis. The signaling pathways involved in the shift from aerobic metabolism to glycolysis in human cancers are also discussed

Topics: Review
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier: oai:pubmedcentral.nih.gov:2660656
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2006). a p53-inducible regulator of glycolysis and apoptosis. Cell
    2. (2009). A tandem duplication in the D-loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies.
    3. (2001). Accumulation of mitochondrial DNA deletions in human oral tissues − effects of betel quid chewing and oral
    4. (1994). Ageing-associated tandem duplications in the D-loop of mitochondrial DNA of human muscle. FEBS Lett.
    5. (2004). Akt stimulates aerobic glycolysis in cancer cells. Cancer Res.
    6. (2004). Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal
    7. (2004). Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma.
    8. (1994). Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors. Cytogenet. Cell Genet.
    9. (2006). Association of decreased mitochondrial DNA content with ovarian cancer progression.
    10. (1997). c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth.
    11. (2006). Cancer's molecular sweet tooth and the Warburg effect. Cancer Res.
    12. (2005). Chloramphenicol-induced mitochondrial stress increases p21 expression and prevents cell apoptosis through a p21-dependent pathway.
    13. (2005). Clinical value of mitochondrial mutations in colorectal
    14. (2006). Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma.
    15. (1998). Co-existence of high levels of a cytochrome b mutation and of a tandem 200 bp duplication in the D-loop of muscle human mitochondrial
    16. (2002). Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res.
    17. (2006). Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs. Oncogene
    18. (2004). Control region mutations and the 'common deletion' are frequent in the mitochondrial DNA of patients with esophageal squamous cell carcinoma.
    19. (1996). Coordinate expression of nuclear and mitochondrial genes involved in energy production in carcinoma and oncocytoma.
    20. (2004). Correlation between clinical characteristics and mitochondrial D-loop DNA mutations in hepatocellular carcinoma.
    21. (2006). Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma.
    22. (2002). CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation.
    23. (2004). Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma. Carcinogenesis
    24. Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells.
    25. (2008). Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability.
    26. (2000). Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc.
    27. (2002). Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients. Clin. Cancer Res.
    28. (2001). Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations. Cancer Res.
    29. (2001). Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res.
    30. (2003). Detection of mitochondrial DNA mutations in the tumors and cerebrospinal fluid of medulloblastoma patients. Cancer Res.
    31. (1996). Detection of mitochondrial genome depletion by a novel cDNA in renal cell carcinoma. Lab Invest.
    32. (1997). Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis. Electrophoresis
    33. (1997). Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ.
    34. (2005). Down-regulation of mitochondrial F1Fo-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res.
    35. (2003). Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations.
    36. (1970). Enzymatic and spectral analysis of cytochrome oxidase in adult and fetal rat liver and Morris hepatoma 3924A. Cancer Res.
    37. (2008). Expression of β-F1-ATPase and mitochondrial transcription factor A and the change in mitochondrial DNA content in colorectal cancer: clinical data analysis and evidence from an in vitro study.
    38. (2002). Extensive somatic mitochondrial mutations in primary prostate cancer using laser capture microdissection Cancer Res.
    39. (2000). Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science
    40. (2007). Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck.
    41. (1988). Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated
    42. (1986). Hexokinase receptor complex in hepatoma mitochondria: evidence from N,N'-dicyclohexylcarbodiimide-labeling studies for the involvement of the pore-forming protein VDAC. Biochemistry
    43. (2004). Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax
    44. (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab.
    45. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab.
    46. (2001). High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res.
    47. (1995). High levels of mitochondrial DNA with an unstable 260-bp duplication in a patient with a mitochondrial myopathy. Neurology
    48. (1999). Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers. Life Sci.
    49. (1994). Human skin mitochondrial DNA deletions associated with light exposure.
    50. (2006). Identification of somatic and germline mitochondrial DNA sequence variants in prostate cancer patients.
    51. Increase in mitochondrial mass in human fibroblasts under oxidative stress and during replicative cell senescence.
    52. (2000). Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells.
    53. (2008). Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells. Prostate
    54. (2005). Increased mitochondrial DNA content in saliva associated with head and neck cancer. Clin. Cancer Res.
    55. (2008). Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells. Oncogene
    56. (1998). Increased sensitivity to cis-diamminedichloroplatinum induced apoptosis with mitochondrial DNA depletion. Cell Death Differ.
    57. (2008). Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line.
    58. (2001). Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev.
    59. (2002). Large deletions in mitochondrial DNA in radiation-associated human thyroid tumors. Cancer Res.
    60. (2004). Less Delta mtDNA 4977 than normal in various types of tumors suggests that cancer cells are essentially free of this mutation.
    61. (2008). Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer.
    62. (2009). Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy.
    63. (2002). Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. Carcinogenesis
    64. (2001). Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma.
    65. (2008). Mitochondria as chi. Genetics
    66. (2005). Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. Gene
    67. (2001). Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion.
    68. (2005). Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress.
    69. (2005). Mitochondrial D-loop mutations and deletion profiles of cancerous and noncancerous liver tissue in hepatitis B virus-infected liver.
    70. (2002). Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma. Clin. Cancer Res.
    71. (2004). Mitochondrial DNA 4,977-bp deletion in paired oral cancer and precancerous lesions revealed by laser microdissection and real-time quantitative
    72. (2006). Mitochondrial DNA 4977 bp deletion mutations in lung carcinoma.
    73. (2001). Mitochondrial DNA alteration in esophageal cancer.
    74. (2006). Mitochondrial DNA determines androgen dependence in prostate cancer cell lines. Oncogene
    75. (1999). Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene
    76. (2003). Mitochondrial DNA mutation correlates with stage progression and prognosis in non-small cell lung
    77. (2005). Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis
    78. (2006). Mitochondrial DNA mutations in human cancer. Oncogene
    79. (2004). Mitochondrial DNA mutations in light-associated skin tumors. Anticancer Res.
    80. (2006). Mitochondrial DNA mutations in oral squamous cell carcinoma. Carcinogenesis
    81. (2006). Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism.
    82. (2004). Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions. Clin. Cancer Res.
    83. (2002). Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors.
    84. Mitochondrial DNA somatic mutations are frequent in nasopharyngeal carcinoma.
    85. (2005). Mitochondrial genome instability and mtDNA depletion in human cancers.
    86. (2006). Mitochondrial mutations in cancer. Oncogene
    87. (2006). Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism.
    88. (2006). Mitochondrial retrograde signaling.
    89. (2004). Mitochondrial signaling: the retrograde response.
    90. (2002). Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene
    91. (2005). Mitochondrial tumour suppressors: a genetic and biochemical update.
    92. (1994). mtDNA and the origin of Caucasians: identification of ancient Caucasian-specific haplogroups, one of which is prone to a recurrent somatic duplication in the D-loop region.
    93. (2005). mtDNA mutations increase tumorigenicity in prostate cancer.
    94. (1999). Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.
    95. (2002). Mutations in the mitochondrial DNA D-Loop region occur frequently in adenocarcinoma in Barrett's esophagus. Oncogene
    96. (2003). Mutations of mtDNA in renal cell tumours arising in end-stage renal
    97. (1996). Novel mitochondrial DNA deletion found in a renal cell carcinoma.
    98. (2005). Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells.
    99. (1956). On respiratory impairment in cancer cells.
    100. (1999). Oncogenic alterations of metabolism.
    101. (2006). Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion. Carcinogenesis
    102. (2007). Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging.
    103. (2005). Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res.
    104. (2008). Progressive tumor features accompany epithelial-mesenchymal transition induced in mitochondrial DNA-depleted cells. Cancer Sci.
    105. (2008). Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases. Breast Cancer Res.
    106. (2007). Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life
    107. (2004). Relationship between mitochondrial DNA instability, mitochondrial DNA large deletions, and nuclear microsatellite instability in head and neck squamous cell carcinomas.
    108. (2007). Relationship between mitochondrial DNA mutations and clinical characteristics in human lung cancer. Mitochondrion
    109. (1997). Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells.
    110. (2004). Resistance of mitochondrial DNA-depleted cells against cell death: Role of mitochondrial superoxide dismutase.
    111. (2008). Resistance of mtDNA-depleted cells to apoptosis. Cytometry A
    112. (1999). Retrograde Ca 2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: A novel mode of inter-organelle crosstalk.
    113. (2008). ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science
    114. (1981). Sequence and organization of the human mitochondrial genome. Nature
    115. (2006). Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer.
    116. (2000). Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours. Oncogene
    117. (2002). Somatic mitochondrial DNA mutations in human chromophobe renal cell carcinomas.
    118. (2004). Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors.
    119. (2004). Somatic mitochondrial DNA mutations in oral cancer of betel quid chewers.
    120. (1995). Somatic mitochondrial mutation in gastric cancer.
    121. (2004). Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma.
    122. (1998). Somatic mutations of the mitochondrial genome in human colorectal tumours.
    123. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell
    124. (2008). Tandem duplication/triplication correlated with poly-cytosine stretch variation in human mitochondrial DNA D-loop region. Mutagenesis
    125. (1996). Tandem duplications and large-scale deletions of mitochondrial DNA are early molecular events of human aging process.
    126. (2002). The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res.
    127. (2009). The frequency of 4977 base pair deletion of
    128. (2005). The increase of mitochondrial DNA content in endometrial adenocarcinoma cells: A quantitative study using laser-captured microdissected tissues.
    129. (1930). The Metabolism of Tumors.
    130. (2007). The mitochondrial DNA common deletion is present in most basal and squamous cell carcinoma samples isolated by laser capture microdissection but generally at reduced rather than increased levels.
    131. (2002). The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res.
    132. (2008). The prevalence of mtDNA 4977 deletion in primary human endometrial carcinomas and matched control samples.
    133. (2004). The role of oxidative stress in carcinogenesis.
    134. (2007). Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production.
    135. (1987). Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription. Science
    136. (2008). Tumor cell metabolism: Cancer's Achilles' heel. Cancer Cell
    137. (2005). Tumor-specific changes in mtDNA content in human cancer.
    138. (2004). Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res.
    139. (2004). Why do cancers have high aerobic glycolysis?

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.