Mitochondrial Deoxyribonucleic Acid (mtDNA), Maternal Inheritance, and Their Role in the Development of Cancers: A Scoping Review

Abstract

Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria as an organelle that could have descended from prokaryotes. This may be the reason for the independent function and inheritance pattern shown by mtDNA. The unstable nature of mtDNA due to the lack of protective histones, and effective repair systems make it more vulnerable to mutations. The mtDNA and its mutations could be maternally inherited thereby predisposing the offspring to various cancers like breast and ovarian cancers among others. Although mitochondria are considered heteroplasmic wherein variations among the multiple mtDNA genomes are noticed, mothers can have mitochondrial populations that are homoplasmic for a given mitochondrial mutation. Homoplasmic mitochondrial mutations may be transmitted to all maternal offspring. However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes, even with homoplasmic mitochondrial populations. Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency witnessed during the transmission of mtDNA from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be demonstrated. Despite initially thought to be limited to the germline, there is evidence that blockages exist in different cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. In this review, we comprehensively discuss the potential mechanisms through which mtDNA undergoes mutations and the maternal mode of transmission that contributes to the development of tumors, especially breast and ovarian cancers.

Keywords: cancer; endosymbiotic theory; inheritance; mitochondrial dna; mtdna.

Figure 1. Endosymbiont theory depicting the evolution of mitochondria from prokaryotes.

Note: This figure has been created by the authors ATP, adenosine triphosphate

Figure 2. Effects of mismatch repair on mitochondrial DNA mutations and cancer.

Note: This figure has been created by the authors MMR, mismatch repair; DNA, deoxyribonucleic acid

Figure 3. Role of ROS in the development of cancer.

Note: This figure has been created by the authors ROS, reactive oxygen species; Rac1, Ras-related C3 botulinum toxin substrate 1; NO, nitric oxide

Figure 4. Role of MT-CYB gene in the development of mitochondrial diseases and cancer.

Note: This figure has been created by the authors MT-CYB, mitochondrial cytochrome b; mtDNA, mitochondrial DNA