**1. Mitochondria and DNA**

Mitochondria are double-membrane organelles that are found in the cytoplasm of most eukaryotic cells, and they are essential for the functioning of tissues that are highly dependent on aerobic metabolism, like the brain and heart, since they produce more than 90% of the energy needed for cellular functions [1]. The human mitochondrial genome (mtDNA) is a double circular molecule of 16,571 pairs of nucleotides (16.5 Kb) which contains 37 genes that code for 22 transfer RNAs, 2 ribosomal RNAs, and 13 subunits that encode mitochondrial DNA. These 13 subunits are key in the respiratory chain and in the oxidative phosphorylation system which contains 7 subunits of complex I, 1 subunit of complex III, 3 subunits of complex IV or cytochrome oxidase, and 2 subunits of complex V or ATP synthase (ATPase6 and ATPase8) (**Figure 1**) [1–3].

#### **1.1. Specific characteristics of mitochondrial genetics**

The type of inheritance of the mitochondrial genetic system, its location in a cytoplasmic organelle, and the continuous arrangement of genes with almost no intermediate nucleotides or introns and polyplasmy (high number of copies in each cell) provide genetic characteristics that clearly differentiate them from those of nuclear DNA. Each cell contains between 1000 and 10,000 copies of mtDNA depending on the tissue, surpassing a few hundred in the sperm and up to 100,000 in the oocyte [4]. Each mitochondrion contains between 2 and 10 molecules. The mtDNA is primarily maternally inherited by a vertical non-Mendelian pattern. Very small amounts of parental mtDNA have been detected; for example, a case of a 28-year-old male with mitochondrial myopathy was reported due to a new 2 bp deletion in the mtDNA of the ND2 gene (also known as MTND2), which encodes a subunit of the complex I enzyme of the mitochondrial respiratory chain. In this study, it was determined that

the mtDNA harboring the mutation was of paternal origin and was calculated to be present

**Figure 2.** Inheritance pattern of mitochondrial DNA. mtDNA is transferred along material lineage; sperm-derived paternal mitochondria enter the oocyte cytoplasm after fertilization but are eliminated from the cytoplasm of gametes.

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The general pattern is that mothers transmit their mitochondrial genome to all of their offspring, but only daughters will pass it on to all of the members of the next generation. This is due to the high number of mtDNA molecules that exist in the ovules (between 100,000 and 200,000 copies) compared to a few hundred in the sperm. In addition, paternal mitochondria

The phenotype of a cell line can vary during cell division because the mitochondria are randomly distributed among daughter cells; so, if in a cell two populations of mtDNA coexist, one normal and one mutated (heteroplasmy), throughout divisions three different genotypes may originate: homoplasmic for normal mitochondrial DNA, homoplasmic for mutated mitochondrial DNA, and heteroplasmic DNA. Therefore, the phenotype of a cell with heteroplasmy will depend on the percentage of mutated DNA it contains. If the number of damaged mtDNA molecules is relatively low, complementation with normal DNA molecules occurs, and the genetic defect will not manifest [8]. When the mutated DNA exceeds a certain threshold, a pathogenic phenotype will develop according to a threshold effect: if ATP production is below the minimum necessary for the functioning of the tissues, due to defective proteins encoded in the mtDNA, illness might develop [7, 9, 10]. The number of DNA molecules is different in each organ and tissue depending on the required energy amounts for functioning. Therefore, the most affected organs and systems are vision, the central nervous system, skeletal muscle, heart, pancreatic islets, kidney, and liver (**Figure 3**) [6, 11, 12].

that enter the fertilized ovum are eliminated by an active process (**Figure 2**) [6, 7].

in 90% of the mtDNA of the patient's muscle [5].

Mitochondrial disease is always related in the maternal line.

**1.2. Mitotic segregation**

**Figure 1.** The mitochondrial genome. Mitochondrial DNA (mtDNA) contains essential genes for normal mitochondrial function, including protein production and electron transport chain (ETC) assembly. This image is a modification of QIAGEN's original [Sánchez-Lopez AL].

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**Figure 2.** Inheritance pattern of mitochondrial DNA. mtDNA is transferred along material lineage; sperm-derived paternal mitochondria enter the oocyte cytoplasm after fertilization but are eliminated from the cytoplasm of gametes. Mitochondrial disease is always related in the maternal line.

the mtDNA harboring the mutation was of paternal origin and was calculated to be present in 90% of the mtDNA of the patient's muscle [5].

The general pattern is that mothers transmit their mitochondrial genome to all of their offspring, but only daughters will pass it on to all of the members of the next generation. This is due to the high number of mtDNA molecules that exist in the ovules (between 100,000 and 200,000 copies) compared to a few hundred in the sperm. In addition, paternal mitochondria that enter the fertilized ovum are eliminated by an active process (**Figure 2**) [6, 7].

#### **1.2. Mitotic segregation**

**1. Mitochondria and DNA**

156 Mitochondrial DNA - New Insights

QIAGEN's original [Sánchez-Lopez AL].

Mitochondria are double-membrane organelles that are found in the cytoplasm of most eukaryotic cells, and they are essential for the functioning of tissues that are highly dependent on aerobic metabolism, like the brain and heart, since they produce more than 90% of the energy needed for cellular functions [1]. The human mitochondrial genome (mtDNA) is a double circular molecule of 16,571 pairs of nucleotides (16.5 Kb) which contains 37 genes that code for 22 transfer RNAs, 2 ribosomal RNAs, and 13 subunits that encode mitochondrial DNA. These 13 subunits are key in the respiratory chain and in the oxidative phosphorylation system which contains 7 subunits of complex I, 1 subunit of complex III, 3 subunits of complex IV or cytochrome oxidase,

and 2 subunits of complex V or ATP synthase (ATPase6 and ATPase8) (**Figure 1**) [1–3].

The type of inheritance of the mitochondrial genetic system, its location in a cytoplasmic organelle, and the continuous arrangement of genes with almost no intermediate nucleotides or introns and polyplasmy (high number of copies in each cell) provide genetic characteristics that clearly differentiate them from those of nuclear DNA. Each cell contains between 1000 and 10,000 copies of mtDNA depending on the tissue, surpassing a few hundred in the sperm and up to 100,000 in the oocyte [4]. Each mitochondrion contains between 2 and 10 molecules. The mtDNA is primarily maternally inherited by a vertical non-Mendelian pattern. Very small amounts of parental mtDNA have been detected; for example, a case of a 28-year-old male with mitochondrial myopathy was reported due to a new 2 bp deletion in the mtDNA of the ND2 gene (also known as MTND2), which encodes a subunit of the complex I enzyme of the mitochondrial respiratory chain. In this study, it was determined that

**Figure 1.** The mitochondrial genome. Mitochondrial DNA (mtDNA) contains essential genes for normal mitochondrial function, including protein production and electron transport chain (ETC) assembly. This image is a modification of

**1.1. Specific characteristics of mitochondrial genetics**

The phenotype of a cell line can vary during cell division because the mitochondria are randomly distributed among daughter cells; so, if in a cell two populations of mtDNA coexist, one normal and one mutated (heteroplasmy), throughout divisions three different genotypes may originate: homoplasmic for normal mitochondrial DNA, homoplasmic for mutated mitochondrial DNA, and heteroplasmic DNA. Therefore, the phenotype of a cell with heteroplasmy will depend on the percentage of mutated DNA it contains. If the number of damaged mtDNA molecules is relatively low, complementation with normal DNA molecules occurs, and the genetic defect will not manifest [8]. When the mutated DNA exceeds a certain threshold, a pathogenic phenotype will develop according to a threshold effect: if ATP production is below the minimum necessary for the functioning of the tissues, due to defective proteins encoded in the mtDNA, illness might develop [7, 9, 10]. The number of DNA molecules is different in each organ and tissue depending on the required energy amounts for functioning. Therefore, the most affected organs and systems are vision, the central nervous system, skeletal muscle, heart, pancreatic islets, kidney, and liver (**Figure 3**) [6, 11, 12].

energy stored in the covalent bonds between ATP phosphates. This last form of potential chemical energy is easily usable by the cell and has been selected throughout evolution as the mechanism by means of which all cellular processes that require the use of energy readily dispose of it [10, 17]. The body must maintain a balance between the needs of cells and the availability of fuel, which is called metabolic homeostasis. The constant availability of fuel in the blood is called caloric homeostasis, whereby the blood level of fuel (in ATP equivalents) does not decrease below certain limits regardless of whether the individual is in a state of good nutrition or fasting. The maintenance of metabolic homeostasis is achieved through the integration of three main factors: (1) the concentration of nutrients in the blood, which affects the speed with which these are used and stored in different tissues, (2) hormone levels in blood (first messengers) that transmit information to specific tissues on the state of the organism and the contribution or demand of nutrients, and (3) the central nervous system (CNS) that by way of neural signals controls the metabolism directly or through the release of hormones [9, 18]. Despite its essential role in the energy metabolism of the brain and other tissues, the amount of circulating glucose is limited. To ensure its continued provision, the body stores metabolic fuels to provide glucose or energy in case of need. Within the homeostatic mechanisms that allow regulation of the availability of combustible molecules, hormonal control is one of the most important. Insulin and glucagon are the main hormones that regulate the storage and use of fuels. Insulin is an anabolic hormone that promotes the storage, while glucagon is the hormone that stimulates the mobilization of the combustible molecules [17, 18]. Other hormones, such as adrenaline, are released as a CNS response to hypoglycemia, exercise, and other types of physiological stress. Along with other stress hormones (glucocorticoids), adrenaline increases the availability of fuels. One of the requirements to maintain and perpetuate life is the preservation of homeostasis, that is, the constancy of the internal environment (blood levels of ions, lipids, and carbohydrates) within narrow limits. These conditions must be maintained even in varied situations such as rest, exercise, satiety, or fasting. How is our body harmonized to survive in different metabolic situations? In mammals, the coordination of metabolism is achieved through the neuroendocrine system. The main hormones involved in the regulation of intermediate metabolism are insulin, glucagon,

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The brain must generate large amounts of ATP to maintain the membrane potential, which is essential for the transmission of nerve impulses. Under normal conditions the brain only uses glucose as fuel, oxidizing it through aerobic glycolysis. It does not use fatty acids. In fact, 60% of the total glucose consumed by the body is used by the brain. The metabolism of the brain is totally aerobic, consuming 20% of the total oxygen consumed by the body. It does not have appreciable reserves of glycogen or other fuels so it requires the constant supply of oxygen

Practically, until adulthood, we are well protected against damage to mitochondria since the body is able to produce antioxidant systems that defend us from it [23]. But as we get older, changes occur inside our cells that determine the progressive destruction of mitochondria

The sequence variations existing between different individuals have been very useful for anthropological, ethnological, and forensic studies and are the basis for the hypothesis that all existing humans descend from a woman who lived in Africa about 250,000 years ago (**Figure 4**) [25–27].

and glucose that cross the blood–brain barrier with ease [19, 22].

and, therefore, bring about aging and disease [24].

catecholamines, and cortisol [19–21].

**Figure 3.** Mitochondrial homoplasmy and heteroplasmy. The expression of mitochondrial diseases is variable; a single cell may receive a uniform collection of mtDNA (homoplasmy) or a mixture of mutant and wild-type mtDNA (heteroplasmy). The proportion of mutant mtDNA molecules determines the penetrance and severity of expression.
