**1. Introduction**

Mitochondria are highly dynamic organelles whose biogenesis and functions are tightly regulated by the nucleus through a constant bidirectional crosstalk. Indeed, only about 1%

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of mitochondrial proteins are encoded by mitochondrial DNA (mtDNA), with all the others encoded by the nuclear genome, including proteins involved in mtDNA replication and transcription [1].

The human mtDNA is a small circular double-stranded DNA molecule of approximately 16.6 kb that encodes for 2 ribosomal RNAs (12S and 16S), 22 transfer RNAs required for protein synthesis and 13 essential protein subunits of the oxidative phosphorylation system (OXPHOS) (**Figure 1**) [2]. The electron transport chain, the primary metabolic pathway which generates energy in the form of ATP, is composed of five protein complexes (I–V) localized in the inner membrane of mitochondria, including complex II that is exclusively coded by the nuclear genome. This system includes seven subunits of respiratory enzyme complex I, one subunit of complex III, three subunits of complex IV and two subunits of complex V. As mentioned before, all other mitochondrial proteins, including those involved in mtDNA replication, transcription and translation, are encoded by nuclear genes and are targeted to the mitochondrion by specific transport systems. The discovery of over 2000 mitochondrial small non-coding RNAs (mitosRNAs), playing a pivotal role in the control of normal mitochondrial gene expression, revealed an underestimated level of mitochondrial functional complexity [3]. Furthermore, studies on antisense anti-termination tRNAs and delRNAs shed new light on novel mechanisms expanding the coding potential of mitogenome [4, 5].

Byproducts of the electron transport chain (ETC) constantly generate reactive oxygen species (ROS) that may severely damage the mitochondrial DNA. If not efficiently repaired, the accumulation of oxidative lesions in the mtDNA molecules lead to gradual mitochondrial dysfunction, which is reflected in changes in the number, morphology and functioning of mitochondria, as observed in cancer cells [6].

mtDNA is more susceptible to mutations than nuclear DNA, due to the lack of histones and chromatin protective structures, paucity of introns, less efficient mtDNA repair mechanisms and a higher exposure to deleterious ROS generated during ATP synthesis within the mitochondrial compartment [7].

> has also been associated with a crucial step for tumorigenesis, that is, epithelial-to-mesenchymal transition (EMT), enabling cancer dissemination and metastatic spread [16]. Importantly, mtDNA alterations may also disrupt the inter-genomic crosstalk between nucleus and mitochondrion and is associated with increased oxidative stress, ROS and cytosolic calcium accumulation, reduction of cell ATP levels and an imbalance in the NADH/NAD+ ratio. Moreover, ROS-induced oxidative stress may also affect the expression of nuclear genes involved in tumorigenic and invasive phenotypes, as it has been shown in colorectal cancer cells [17].

> **Figure 1.** Map of the human mitochondrial DNA and distribution of somatic variants in colorectal cancer. mtDNA somatic mutations are mainly represented by homoplasmic alterations (black arrowheads), although rarer heteroplasmic substitutions (blue arrowheads) have been detected in the MT-RNR2 (16S) region or mixed homoplasmic/heteroplasmic

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

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Cancer is caused by the accumulation of multiple genetic alterations, such as point mutations, copy number variations (CNVs), inversions and epigenetic modifications [18]. This multi-step

**2. mtDNA alterations: a focus on colorectal carcinogenesis**

**2.1. Somatic mtDNA variants**

variants (red arrowheads) in the MT-ND5 locus.

Although low levels of intracellular ROS normally regulate cellular signaling and are essential for normal cell survival and proliferation, aberrant ROS production is frequently observed in neoplastic cells. In the mitochondrial free radical theory of aging accumulation of damaging mtDNA mutations, impairment of oxidative phosphorylation as well as an imbalance in the expression of antioxidant enzymes results in exponential overproduction of ROS. This elicited condition forms a "vicious cycle" that is the basis of a wide range of pathologies, termed as "free radical diseases" such as cancer, neurodegeneration, atherosclerosis, diabetes mellitus and chronic inflammation [8]. Importantly, besides the obvious induction of oxidative nucleotide damage to mtDNA, ROS promotes tumorigenesis through several other mechanisms, including stabilization of hypoxiainducible factor (HIF)-α, increased calcium flux, inactivation of key phosphatases, such as Pten and PP2A, and activation of both the NRF2 and NF-κB transcription factors [9–11].

Since the Warburg theory of cancer postulated in 1956 [12], mitochondrial dysfunction has been regarded as a hallmark of cancer progression and as a promising target for anticancer t herapies [13, 14]. For instance, enhancing complex I activity has been demonstrated to inhibit tumorigenicity and metastasis of breast cancer cells [15]. More recently, mitochondrial dysfunction

Mitochondrial DNA Variations in Tumors: Drivers or Passengers? http://dx.doi.org/10.5772/intechopen.75188 197

**Figure 1.** Map of the human mitochondrial DNA and distribution of somatic variants in colorectal cancer. mtDNA somatic mutations are mainly represented by homoplasmic alterations (black arrowheads), although rarer heteroplasmic substitutions (blue arrowheads) have been detected in the MT-RNR2 (16S) region or mixed homoplasmic/heteroplasmic variants (red arrowheads) in the MT-ND5 locus.

has also been associated with a crucial step for tumorigenesis, that is, epithelial-to-mesenchymal transition (EMT), enabling cancer dissemination and metastatic spread [16]. Importantly, mtDNA alterations may also disrupt the inter-genomic crosstalk between nucleus and mitochondrion and is associated with increased oxidative stress, ROS and cytosolic calcium accumulation, reduction of cell ATP levels and an imbalance in the NADH/NAD+ ratio. Moreover, ROS-induced oxidative stress may also affect the expression of nuclear genes involved in tumorigenic and invasive phenotypes, as it has been shown in colorectal cancer cells [17].
