Mutations in Mitochondrial DNA and Cancer (Research Paper Sample)

Are Mutations in Mitochondria DNA important in Cancer and can ‘Three-Parent IVF’ be a Potential Cure?
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1. Introduction
The mitochondria are the sources of energy in the human cell. This energy is generated through the mitochondrial respiratory chain and is presented in the form of Adenosine triphosphate (ATP). Besides energy synthesis, the organelles perform other roles such as the formation of heme and cholesterol, and the regulation of apoptosis. The mitochondria are found in every cell of the body except the red blood cells. Unlike other organelles, the mitochondria contain their own DNA (mtDNA) and genetic code that encode the synthesis of proteins. The mtDNA is susceptible to alterations, resulting in disorders such as Kearns-Sayre syndrome (KSS), mitochondrial encephalopathy with lactic acidosis, chronic progressive external ophthalmoplegia (CPEO), Leigh syndrome (LS), and cancers, 7, 8, 9 among others. Cancers emanating from mtDNA mutations usually affect 1 in every 4000 individuals in America5, and is maternally inherited. The implication of the maternal involvement the transmission of mtDNA mutations has necessitated scientists to come up with management practices that will halt the maternal transmissions. The “The Three-Parent In-Vitro Fertilization” (“Three-P IVF”). Is among the current management practices for mtDNA disorders. As a result, this paper intends to look at the efficacy and effectiveness of the “Three-P IVF” versus existing controls in the management of disorders resulting from mtDNA mutations.
2. The Mitochondria and Mitochondrial DNA
The mitochondria are the only organelles capable of synthesizing energy in the cell. The organelles are located in the cytoplasm of the cell and perform activities such as cellular metabolism to generate energy, modulate cell death through apoptosis and the synthesis of heme and cholesterol. 2,3,4,6.9,10 The organelles are semi-autonomous with a double layer and prominent folded structure called cristae. The outer membrane has porins that facilitate the passage of smaller molecules and a large multiprotein translocase complex that allows the passage of the molecules through signal transductions. 2,3,4,6 The inner membrane has components for the electron transport system and the ATP Synthase complex.6, 10 The highly folded inner membrane contains a matrix that houses the mtDNA.6
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Fig 1: An illustration of the fundamental structure and functional aspects of the mitochondria10 The mitochondrial genome contributes polypeptide subunits that make the oxidative phosphorylation system.
The major function of the mitochondria is to synthesize energy for the cell. The process of energy synthesis takes place in the cytoplasm. Energy generation occurs through oxidative phosphorylation (OXPHOS) cycle, aided by a chain of protein complexes known as the respiratory chain. 9, 10 This is done by oxidizing the major products of glucose, pyruvic acid, and NADH, commonly produced in the cytosol. The process is highly efficient, incorporating protein products from the nuclear and mitochondrial genome. During mitochondrial mutations, the OXPHOS is defective, allowing a compensatory mechanism in the glycolytic pathway.6 This way, the cell is able to continuously generate energy.
Furthermore, the organelles are involved in apoptosis and cell survival. 9, 10 The mitochondria is a store for pro-apoptotic proteins encoded by the nuclear DNA. Some of these proteins include cytochrome c, endonuclease G, apoptosis-inducing factor, as well as the smac/DIABLO10 and they accomplish unidentified physiological tasks. The release of the proteins from the mitochondria triggers biochemical cascades that result in the activation of the apoptotic pathway. 6,9,10
The mitochondrial genome is composed of a double-stranded DNA that encodes the mitochondrial proteins.4, 5, 9, 10, 17, 18The helical structure of the mtDNA is similar to that of the nuclear DNA (nDNA). The genetic material is located in the matrix of the mitochondria, 2, 6 and differs slightly from the nuclear DNA. The mtDNA is circular, while the nDNA is linear; and is built on 16589 base pairs, while the nDNA has 3.3 billion base pairs. 11, 12, 13 Furthermore, the genomic structure of the mtDNA possess 37 genes that code 13 proteins, two ribosomal RNA and twenty two transfer RNA, 9, 10 which facilitate the energy generating function of the mitochondria. However, the dependence of the mitochondria on imported gene products from the nucleus makes it semi-autonomous regarding energy generation and other roles.


Fig 2: An illustration of the mitochondrial genome in energy generation.11 The genes encode the proteins required for energy generation through the oxidative phosphorylation cycle.
3. Mitochondrial Mutations Leading to Cancer
3.1 Mitochondrial mutations
The mtDNA shows a higher mutation rate than the nuclear DNA.1, 2, 4, 6, 11, 13 This is attributed to the nucleotide imbalance present in mtDNA compared to nDNA. 9, 11, 13 There is a general consensus among researchers that the nuclear imbalance found in mtDNA could be responsible for the compromised fidelity of the POLG protein encoded by the DNA polymerase enzyme. The protein has two parts; the catalytic part that executes the functions of the DNA polymerase and the exonuclease part whose role lies in the removal of the base-pair miss-matches. 11, 12, 13, 14 As a result, the mtDNA ends with a higher fold of mutations, leading to generation of heterogeneous mtDNA populations within the same cell.9, 11, 12, 13, 14 Therefore, in the process of replication, the daughter cells receive similar but non-identical copies of genetic material, leading to mitochondrial diseases.
It has been postulated that mutations in the mtDNA arise mainly because of the lack of protective mechanisms in the mitochondria, predisposing the DANA to damaging agents such reactive oxygen species and its close proximity to the electron transport chain.1, 2, 3, 4, 5, 6 The DNA damaging agents could lead to deletion, insertion, and duplication of the mtDNA genome responsible for encoding specific genes. Furthermore, the presence of many mitochondria in an individual cell facilitates the existence of the mutant variant of DNA with normal mtDNA in a condition called heteroplasmy. 10
Mitochondrial mutations are mainly passed along the maternal line. 9, 10, 11,12,13,14. Maternal transmissions are the dominant ways of acquiring mitochondrial abnormalities, although this transmission depends on the nature of the mutation.6 Homoplasmic mtDNA mutations are likely to be transmitted to the offspring, and among the offspring that inherit this mutation, only some will develop the disease.10 Among the offspring with homosplamic mutations, close to 50% of the male offspring will get the disease, while only 10% of the females are likely to acquire the disease. Heteroplasmic mtDNA mutations also occur, but involve a complex interaction of the nuclear factors and the environmental factors.6, 10 As a result, the offspring ends up with disorders such as Kearns-Sayre syndrome (KSS), neurogenic weakness with ataxia, Leigh syndrome, chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis,7, 8, 9 among others. For the cancers, almost of them are attributed to mtDNA mutations.


Figure 3: A representation of the mitochondrial genome and the mitochondrial biogenesis. The mtDNA is packaged into the nucleoid and its replication facilitated by the DNA polymerase γ (pol-γ). It encodes 13 proteins, 22 tRNAs, and 12S and 16S rRNAs 4
Cancer
Chromosome
Gene
Risk Allele
Pathway
Symptoms
Breast cancer 10,11,12,13
Maternal chromosome X
16S RNA, ND2, ATPase 6, Cytochrome cm.3271T>C
m.8356T>C
m.10010T>C
m.8993T>COxidative phosphorylationNeurogenic weakness, migraine, peripheral neuropathy, dysphagia, myalgia, cardiomyopathy1,6,10Ovarian Cancer 10Maternal chromosome XD-loop, 12S rRNA, 16S rRNA, Cytochrome bm.3460G>A
m.1606G>A
m.3243A>G
m.1555A>GProtein SynthesisMyalgia, cardiomyopathy, arthralgia, ataxia, peripheral neuropathy 6,10,18Colorectal Cancer 13,14,15,16Maternal chromosome X12S rRNA, 16S rRNA, COX I, II, III, Cytochrome b, ND1, ND4L, and ND5.m.14709T>C
m.5386T>C
m.4274T>COxidative PhosphorylationMyalgia, myopathy, lack of appetite, ataxia, psychomotor retardation, ptosis, optic neuropathy 6,10Solid tumors, hepatic cancers, renal cancers, and brain tumors 2,3,4Maternal chromosome XD-loopm.11778G>A
m.1606G>A
m.14709T>C
m.12320A>G
m.3243A>GTranscriptionMyopathy, cardiomyopathy, psychomotor retardation, ataxia, myalgia, peripheral neuropathy 6,10,18Table 1: Comparisons of cancers caused by mutations in mtDNA. Most of the stated cancers are caused by errors in DNA replication, protein synthesis, and aerobic respiration.
3.2 Other Causes of Mitochondrial-Derived Cancers
There is a strong link between cancer, the environment and individual genes. From conception through adolescence to old-age, an individual get exposed to several pro-carcinogenic agents in the environment. Some of the agents include radiations, exposure alkylating agents, exposure to microbes such as fungi and viruses, as well as sunlight exposure. 18,19,20,21 Depending on the individual’s gene polymorphism, they can get cancer or not. The implications of diet have not escaped the attention of researchers who contend that inadequate fruit and vegetable intake, as well as essential amino acids is likely to lead to cancer.17 As a result, the interplay be...