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Mitochondrial DNA Mutations in Cancer

PLoS Medicine
Public Library of Science
Publication Date
DOI: 10.1371/journal.pmed.0020401
  • Perspectives
  • Cancer Biology
  • Cell Biology
  • Oncology
  • Biology
  • Chemistry
  • Medicine


PLME0211_1082-1084.indd PLoS Medicine | 1082 In 1956, the German biochemist and Nobel Laureate Otto Warburg proposed that cancer is caused by altered metabolism and by deranged energy processing in mitochondria [1]. After falling on deaf ears for decades, his theory has recently enjoyed a resurrection, coinciding with an explosion of new information on the role of mitochondria in energy metabolism and oxygen sensing. Mitochondrial Enzyme Defi ciencies in Inherited Neoplasia Mitochondrial defects have been associated with severe neurodegenerative disorders [2], and, more recently, with primary hereditary neoplasias. Germline heterozygote mutations in the nucleus-encoded mitochondrial succinate dehydrogenase (SDH) subunits—a tricarboxylic acid cycle (TCA) enzyme, which is also part of the respiratory chain—cause inherited pheochromocytomas and paragangliomas. Mutations in another TCA enzyme, fumarate hydratase (FH), cause cutaneous and uterine leiomyomas, as well as renal cell carcinomas [3]. Mitochondrial proteins may also play a role in the development of the sporadic kidney tumor oncocytoma [4]. Selak et al. has recently shed light on the mysterious connection between tumors and SDH/ FH [5]; they showed that the hypoxia- inducible factor (HIF)–mediated signaling pathway, known to be tumorigenic in von Hippel Lindau syndrome, also plays a role in SDH and FH defi ciency (Figure 1) [5]. Somatic mtDNA Mutations in Sporadic Tumors Mitochondrial DNA (mtDNA) mutations have also been linked to nonhereditary tumors. Intragenic deletions (see Glossary) [6], missense and chain-terminating point mutations [7], and alterations of homopolymeric sequences [8] have been identifi ed in nearly every type of tumor. Mutations have been described in the hypervariable regions of the mitochondrial D-loop, the section of DNA controlling mtDNA transcription and replication that is most prone to mutation. Mutations have also been de

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