Are mutations in mitochondria DNA important in cancer and can ‘Three-Parent IVF be a potential cure?

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nThe Mitochondria

nMitochondria are special structures in the cells of fungi, plants and animals. They act as source of power by providing energy to different cells functions and the rest of the body. The structure of mitochondria is capsule shaped. In addition, it has double membrane i.e. inner and outer membrane. The inner membrane forms cristae, which increase the surface area of the membrane (Schon, Dimauro and Hirano 2012, p. 61). Unlike other cell organelles, mitochondria have their own genes and DNA that are responsible of encoding proteins.

nMitochondria are very important in the cell because they metabolize fatty acids and carbohydrates to produce energy. Energy that is produced is stored in form of Adenosine triphosphate (ATP) (Gorman, Grady, Ng, Schaefer and Mcnally, 2015, p. 31). The ATP is synthesized in the mitochondria matrix. The process of production of energy in the mitochondria is referred to as oxidative phosphorylation. Mitochondria have another function of synthesizing proteins for their use. The protein is used for transcriptions of DNA to RNA (Villanueva 2015, p. 11). Furthermore, mitochondria have other roles such as apoptosis. This process helps mitochondria to regulate the cells through self-destruction. They also play a critical role in production of heme and cholesterol (Chiaratti, Meirelles, Wells and Poulton 2011, p. 22).

nOn the other hand, the mitochondrial DNA is a genetic material that is found in the mitochondria. It is made up of thirty-seven genes that play a role in normal mitochondrial functions. In addition, out of these genes, thirteen of them are used to give instructions in enzymes production during oxidative phosphorylation (Singh and Costello 2009, p. 14). Moreover, the rest play an essential role in provision of instructions for manufacturing ribosomal RNA and transfer RNA. RNA is important because they assist in production of proteins from amino acids (Copeland, 2014, p. 18).

nMitochondrial Mutations leading to Cancer

nMitochondrial mutations are defects that occur in the mitochondrial which facilitate the progression and development of cancer. The process of apoptosis facilitates the development of cancer and the ability of cells to respond to anticancer agents. Through the process of oxidative phosphorylation, mitochondria generate more energy in the cells. In this process, oxidation of hydrogen takes place to produce water and ATP (Majuri and Kroemer 2015, p. 25). Furthermore, the by-products of this reaction include reactive oxygen species (ROS). Since the mitochondria, DNA is very close to the production sites of ROS, it is very easy for oxidative injury to occur. Therefore, this may increase the chance for mitochondria DNA mutations to occur which ultimately lead to cancer (Singh and Costello 2009, p. 19). Research has indicated that mutations occur in both coding and non-coding regions of the mitochondria DNA. Addition, most of the mutations seem to be homoplastic in nature i.e. it occurs in all types of human tissues.

nThe reactive oxygen species are responsible for the progression of mitochondria mutations. According to Desideri, Vegliante, and Cirilio (2015) high levels of ROS are observed in cancer cells. However, the progression of cancer encompasses many mechanisms such as hypoxia, which contribute to high levels of ROS, oncogenes and hypoglycaemia (Desideri, Vegliante, and Cirilio 2015, p. 12). Most importantly, this process leads to mitochondria DNA mutations. Moreover, the metastatic potential of the respiratory chance contribute to higher levels of ROS, which consequently leads to tumour growth in cancer cells (Schon, Dimauro and Hirano 2012, p. 65).

nGeneral mitochondrial diseases that can occur due to mitochondrial mutations include breast cancer, colorectal cancer, ovarian cancer, gastric carcinoma, hepatocellular cancer, lung cancer, prostate cancer and brain cancer (Villanueva 2015, p. 21). For instance, researches have indicated that there is high level of mitochondria mutations in breast cancer. Some of these mutations were insertions, deletions or single-base substitutions in different codes. However, single-base substitutions comprised the highest percentage of mutations at 58 per cent while deletions and insertions comprise 42 per cent (Gorman, Grady, Ng, Schaefer and Mcnally, 2015, p. 31). In other studies, it was reported that the D310 region in the DNA comprised 42 per cent of the mutations, which were involved in the control region (D-loop). Symptoms of breast cancer begin with abnormal mammogram or breast lump (Majuri and Kroemer 2015, p. 33). There are several stages of breast cancer, which include metastatic breast cancer, curable breast cancer, and early breast cancer. Due to cancer, the shape or size of one or both breasts may change. The nipples may change their appearance (Verschoor, Ungard, Harbottle Jakupciak, and Parr 2013, p. 21).

nOther causes of mtDNA mutations include the environmental factors and genetics. Studies have indicated that hereditary factors contribute to cancer development and progression. Genes from either parent can pass to the offspring, which ignite the cancer (Greaves, Reeve, Taylor and Turnbull 2012, p. 10). For instance, one in every 4 000 children born in the United States have inherited mitochondria diseases. In addition, mitochondria can be caused by environmental factors such as hazardous radiation, which can trigger cancer (Schon, Dimauro and Hirano 2012, p. 71). For instance, gamma and x-rays are causal agents of cancer. Moreover, sedentary lifestyle, poor diet and habitat can contribute to cancer to mutations in the mtDNA.

nThe ‘Three-Parent IVF – a potential cure?

nThe three parent in vitro fertilization is a fertility process that helps to develop an embryo utilizing the DNA material from three persons: an egg donor and the parents. The essence of three-parent IVF is to replace the faulty genes in the mums mitochondria and replacing them with healthy genes in order to prevent deadly diseases. In the normal process of conception, a fertilize egg comprises DNA from both the father and mother genes. Three parents IVF is also referred to as mitochondrial replacement therapy (Majuri and Kroemer 2015, p. 59). Therefore, the therapy enables affected mothers to have healthy babies that are genetically associated with them. During this procedure, the standard IVF treatment is applied in order to gather eggs from the mother. Consequently, nucleus from one of the mothers egg is removed and it is transferred to a healthy donor egg. Doctors also remove the nucleus from the donors egg (Kmietowicz 2015, p. 10). The new egg has mothered nuclear DNA that is health and has 99.9 per cent of her genes. In addition, the new egg has healthy mitochondria from a donor. After this process is complete, the sperms from the father then fertilize the reconstituted egg. Finally, the doctors then implant the embryo into the woman similar to any other IVF embryo (Brown, Herbert, Lamb, Chinnery, and Taylor, 2006, p. 10).

nAlthough few persons have the problem of mitochondrial diseases but their effects are usually overwhelming. Mitochondrial diseases cause problems such as muscular dystrophy, heart problems and neurological conditions. Furthermore, pregnant mothers carrying DNA mutations are exposed to multiple miscarriages (Taylor and Turnbull 2005, p. 19). Most importantly, a child suffering from these conditions have a higher risk to suffer greatly. Therefore, many children having this problem do not survive beyond their childhood (Amato, Tachibana, Sparman, Mitalipov 2014, p. 33).

nThree-parent IVF has been adopted by some countries across the world. The process involves replacement of a single strand of the DNA from the mother with another DNA from a healthy donor. DNA in the cell nucleus control Characters such as eye colour and hair. The benefits of this therapy are that it saves millions of lives. In addition, it prevents complications such as heart conditions, blindness and muscular dystrophy. In 2016, the world expects to receive the first child through this process (Kmietowicz 2015, p. 39). For instance, countries such as the United Kingdom have allowed the use of this technique because it offers more benefits. In other countries such as the US, the technology is not easily available because it is expensive hence some people are not able to access it (Wallace 2012). The three-parent IVF procedures have not indicated any side effects. Scientists have tested the results in both human beings and animals. The IVF process is not associated with any type of risk because the DNA is donated from a healthy woman. However, mitochondrial transfer has faced many objectives from the religious groups and from ethical viewpoints. Since the three-parent IVF transfers genetic material from one generation to the other, it raises the ethical concerns (Amato, Tachibana, Sparman, Mitalipov 2014, p. 36). For instance, the procedure may lead to unexpected problems. Consequently, this process may affect unborn persons. Furthermore, unborn persons do not give a right to give the consent to use the treatment.

nMoreover, since the mitochondria and its DNA are not fully understood the three-parent therapy may produce human traits in unknown ways. In this respect, many scientists object the procedure until such a time the mitochondria will be understood before legalization. Religious leaders especially in the UK argue that more scientific debate and research should be conducted prior to legalization of the law in order to determine its efficacy and safety (Amato, Tachibana, Sparman, Mitalipov 2014, p. 40).

nMoreover, three-parent IVF has also received criticism from the Catholic Church. The church argues that the procedure is not right because the procedure destroys a fertilized egg from a mother. Additionally, the church argues that mitochondrial transfer destroys parenthood (Carew and Huang 2002, p. 15).

nOther treatments and prevention strategies

nCurrently, there are different strategies that are used to treat mitochondrial DNA disease. Some of these methods are effective depending on early detection of the disease. For instance, they include satellite cells, illogic expressions, amniocentesis, chorionic villus biopsy, and polar body. Satellite cells are a group of quiescent cells that are found between the plasma lemma and lamina of muscle fibre (Appleby 2015, p. 28). They help in treatment of mitochondrial diseases. Moreover, chorionic villus biopsy is conducted in early pregnancy in order to gather biochemical and genetic analysis. On the other hand, enhancing genetic information and advice is used to prevent progression and development of cancer. In this regard, techniques such as chorionic villus biopsy and amniocentesis are applied in order to identify mtDNA disorders prior to development of cancer (Gaude and Frezza 2014, p. 23).

nThese techniques are different as compared to Three-Parent IVF. For instance, these method do not involve the transmission of genetic material from one cell to another. In addition, the current methods do not have the ability to transfer therapeutic materials into a cell in order to prevent cancer (Copeland, 2014, p. 24). Furthermore, three-parent IVF is similar to current methods because it seeks to complement faulty mitochondrial gene with a healthy type of genes. They are also similar because they are able to identify cells in a mother that require therapy.

nThree-parent IVF has more benefits as compared to the current treatment strategies. The procedure is beneficial because it helps to prevent mitochondrial DNA diseases across world. The current strategies do not offer reliable cure of this problem (Yabuuchi, Beyhan, Kagawa, Mori and Ezoe 2012, p. 52). It helps reduce the infant mortality rate hence children are able to develop up-to adulthood. However, the weakness of this procedure is that it is expensive hence; people in low socioeconomic background cannot access it (Appleby 2015, p.33).

nConclusion

nThe mitochondria play an essential role in energy generation in human body. They also contain genetic material referred to as mtDNA. However, mutations in the michondrial DNA are responsible for cancer in childhood. Cancer can be caused by genetics, and environmental factors. Fortunately, the three-parent IVF is a new technology that is capable of transferring a nucleus from a mother to another cell of a donor. The donor cell provides mitochondria. The technique is important because it reduces the complications associated with mitochondrial mutations, which affects the liver, heart, muscles and brain among children. The shortcoming of this procedure is that some of it harmful effects to the baby have not been identified. In addition, it is very expensive to use (Máximo, Lima and Soares 2009, p. 10).

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nReferences

nAmato P, Tachibana M, Sparman M, Mitalipov S. 2014. Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases. Fertility and Sterility.;101(1): 31-35.

nAppleby J.B. 2015. The ethical challenges of the clinical introduction of mitochondrial replacement techniques. Medicine, Health Care and Philosophy.;18(4): 501-514.

nBrown DT, Herbert MV, Lamb K, Chinnery PF, and Taylor RW. 2006. Transmission of mitochondrial DNA disorders: possibilities for the future. The Lancet.;368(9529): 87-89.

nCarew JS, and Huang P. 2002. Mitochondrial defects in cancer. Molecular cancer.;1(1): 9.

nChiaratti MR, Meirelles FV, Wells D, and Poulton JP. 2011. Therapeutic treatments of mtDNA diseases at the earliest stages of human development. Mitochondrion.;11(5): 820-828.

nCopeland W.C. 2014. Defects of Mitochondrial DNA Replication. Journal of Child Neurology.;29(9): 1216-1224.

nDesideri E, Vegliante R, and Cirilio M.R. 2015. Mitochondrial dysfunctions in cancer: genetic defects and oncogenic signaling impinging on TCA cycle activity. Cancer letters.;356(2): 217-223.

nGaude E, and Frezza C. 2014. Defects in mitochondrial metabolism and cancer. Cancer & metabolism.;2(1): 10.

nGorman G.S, Grady G.P, Ng Y, Schaefer A.M, and Mcnally R.F. 2015. Mitochondrial Donation — How Many Women Could Benefit? The New England journal of medicine.;372(9): 885-887.

nGreaves L.C, Reeve A.K, Taylor R.W, and Turnbull D.M. 2012. Mitochondrial DNA and disease. The Journal of Pathology.;226(2): 274-286.

nKmietowicz Z. 2015. UK becomes first country to allow mitochondrial donation. BMJ (Clinical research ed). [Online] 2015;350(H1103): . Available from: http://www.bmj.com.ezproxy.brad.ac.uk/content/bmj/350/bmj.h1103.full.pdf [Accessed 03 October 2015].

nMajuri M.C, and Kroemer G. 2015. Essential role for oxidative phosphorylation in cancer progression. Cell metabolism.;21(1): 11-12.

nMáximo V, Lima J, and Soares P. 2009. Mitochondria and cancer. Virchows Archiv.;454(5): 481-495.

nSchon E.A, Dimauro S, and Hirano M.R. 2012. Human mitochondrial DNA: roles of inherited and somatic mutations. Nature reviews Genetics.;13(12): 878.

nSingh, K. and Costello, L., 2009. Mitochondria and cancer. New York: Springer.

nTaylor RW, and Turnbull DM. 2005. Mitochondrial DNA mutations in human disease. Nature Reviews Genetics.;6(5): 389-402.

nVerschoor ML, Ungard R, Harbottle A, Jakupciak JP, and Parr RL. 2013. Mitochondria and Cancer: Past, Present, and Future. BioMed research international; (1): 1-10.

nVillanueva M.T. 2015. The mitochondria thief. Nature reviews Cancer.;15(2): 70.

nWallace DC. 2012. Mitochondria and cancer.. Nature reviews Cancer.;12(10): 685-695.

nYabuuchi A, Beyhan Z, Kagawa N, Mori C, and Ezoe K. 2012. Prevention of mitochondrial disease inheritance by assisted reproductive technologies: Prospects and challenges. Biochimica et Biophysica Acta (BBA) – General Subjects.;1820(5): 637-642 .