Somatic mitochondrial DNA mutations in human cancers

Adv Clin Chem. 2012;57:99-138. doi: 10.1016/b978-0-12-394384-2.00004-8.


Mitochondria are ubiquitous organelles in eukaryotic cells principally responsible for regulating cellular energy metabolism, free radical production, and the execution of apoptotic pathways. Abnormal oxidative phosphorylation (OXPHOS) and aerobic metabolism as a result of mitochondrial dysfunction have long been hypothesized to be involved in tumorigenesis. In the past decades, numerous somatic mutations in both the coding and control regions of mitochondrial DNA (mtDNA) have been extensively examined in a broad range of primary human cancers, underscoring that accumulation of mtDNA alterations may be a critical factor in eliciting persistent mitochondrial defects and consequently contributing to cancer initiation and progression. However, the roles of these mtDNA mutations in the carcinogenic process remain largely unknown. This review outlines a wide variety of somatic mtDNA mutations identified in common human malignancies and highlights recent advances in understanding the causal roles of mtDNA variations in neoplastic transformation and tumor progression. In addition, it briefly illustrates how mtDNA alterations activate mitochondria-to-nucleus retrograde signaling so as to modulate the expression of relevant nuclear genes or induce epigenetic changes and promote malignant phenotypes in cancer cells. The present state of our knowledge regarding how mutational changes in the mitochondrial genome could be used as a diagnostic biomarker for early detection of cancer and as a potential target in the development of new therapeutic approaches is also discussed. These findings strongly indicate that mtDNA mutations exert a crucial role in the pathogenic mechanisms of tumor development, but continued investigations are definitely required to further elucidate the functional significance of specific mtDNA mutations in the etiology of human cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Nucleus / physiology
  • DNA, Mitochondrial / drug effects
  • DNA, Mitochondrial / genetics*
  • Disease Progression
  • Humans
  • Mutation / genetics
  • Mutation / physiology*
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Receptor Cross-Talk / physiology


  • Antineoplastic Agents
  • DNA, Mitochondrial