Mitochondrial Subversion in Cancer

Abstract

Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA (mtDNA) mutations in the regulatory D-loop region and somatic mtDNA mutations are common in primary human cancers. The biological impact of a given mutation may vary, depending on the nature of the mutation and the proportion of mutant mtDNAs carried by the cell. Identification of mtDNA mutations in precancerous lesions supports their early contribution to cell transformation and cancer progression. Introduction of mtDNA mutations in transformed cells has been associated with increased ROS production and tumor growth. Studies reveal that increased and altered mtDNA plays a role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. This review offers some insight into the extent of mtDNA mutations, their functional consequences in tumorigenesis, mitochondrial therapeutics, and future clinical application.

Additional cytosine inside mitochondrial C-tract D-loop as a progression risk factor in oral precancer cases

“…Considering mtDNA lacks introns, most mutations occur in the coding sequences and are thus, likely to be of biological consequence. 20 mtDNA mutations can be either deleterious (pathogenic), neutral or beneficial (adaptive). Positive selection of an adaptive mutation in the mtDNA leads to its enrichment in the population.…”

“…It is postulated that alteration in the number of cytosine residues in the Poly-Cytosine region may affect the mtDNA replication rate by impairing the binding of polymerase and other transacting factors. 20,24 Mitochondrial DNA is 10e100 times more vulnerable to mutations than nuclear DNA due to lack of histone protection, limited repair capacity and close proximity to the electron transport chain which constantly generates superoxide radicals. Tobacco carcinogens are known source of oxidative stress and thus may have central role in promoting mitochondrial genomic instability.…”

Somatic mutations in the D-loop of mitochondrial DNA in oral squamous cell carcinoma

“…It was also found that mutations in mtDNA played a role in the development of cancer [16]. Although mutation in mtDNA might be involved in the carcinogenesis, it did not necessarily have impact on the survival.…”

Hepatocellular Carcinoma: Epidemiology and Etiology

“…This feature is also described in rapidly dividing embryonic tissues, even though they are able to switch to oxidative metabolism as proliferation ceases and cells differentiate, suggesting that cancer development may be understood as altered embryonic development (Barger & Plas, 2010, Cooper, 2009, Soto & Sonnenschein, 2004. As a result of Warburg's observations, defects in mitochondrial function have been suspected as contributing to cancer development and progression (Chatterjee et al, 2011). Recently, not only mitochondria but also endoplasmic reticulum have been found to be implicated in controlling the lipid metabolism, in particular in the liver.…”