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.

Role of the mitophagy‐apoptosis axis in the pathogenesis of polycystic ovarian syndrome

“…However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes based solely on mitochondrial genetic mutations. 68 Genetic predisposition explains less than 10% of cases, so genetic abnormalities alone are unlikely to directly cause the disease. 61,66,[69][70][71][72][73] Despite recent advances in the molecular biology, no PCOS susceptibility genes or candidate genes have been identified to explain the inheritance pattern.…”

“…mtDNA First, the mammalian mtDNA encodes 2 ribosomal RNAs, 12S rRNA and 16S rRNA, and 13 oxidative phosphorylated subunit proteins. 3,66,68,96 These proteins facilitate the synthesis of ATP by ATP synthase in the…”

The Role of Epigenetic Control of Mitochondrial (Dys)Function in MASLD Onset and Progression

“…It is important to remark that the mitochondrial genome displays peculiar features, such as the absence of protective histones that account for a different spatial organization with respect to nuclear DNA [49,50].…”

Exosomal DNA: Role in Reflecting Tumor Genetic Heterogeneity, Diagnosis, and Disease Monitoring

“…In a study conducted by Judit et al [ 61 , 62 ], exoDNA was extracted from blood and plasma samples of 24 patients with serous epithelial ovarian cancers and 24 healthy control subjects. The researchers utilized real-time quantitative PCR to measure the copy numbers of mtDNA.…”

“…The increased levels of both free-cell and exosomal mtDNA in advanced cancer align with the characteristics of tumor-derived DNA promoting metastasis [ 65 ]. It can be concluded that an altered mtDNA copy number might serve as a signal for cancer progression in ovarian cancer [ 62 , 63 , 64 ]. Further research will be needed to validate these findings and explore the clinical utility of mtDNA copy number as a biomarker in ovarian cancer patients [ 66 ].…”