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MITOCHONDRIA The mitochondria is a double-membrane-bound organelle found in most eukaryotic organisms. Some cells in some multicellular organisms may, however, lack them (for example, mature mammalian red blood cells). A number of unicellular organisms, such as microsporidia, parabasalids, and diplomonads, have also reduced or transformed their mitochondria into other structures. The Word mitochondrion comes from the Greek word mitos, "thread", and chondrion, "granule" or "grain-like". Mitochondria generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. A mitochondria was thus termed the powerhouse of the cell. Mitochondria are commonly between 0.75 and 3 μm in diameter but vary considerably in size and structure. Unless specifically stained, they are not visible. The number of mitochondria in a cell can vary widely by organism, tissue, and cell type. For instance, red blood cells have no mitochondria, whereas liver cells can have more than 2000. Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome that shows substantial similarity to bacterial genomes. A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins. The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. They are: 1. the outer mitochondrial membrane, 2. the intermembrane space (the space between the outer and inner membranes), 3. the inner mitochondrial membrane, 4. the cristae space (formed by infoldings of the inner membrane), and 5. the matrix (space within the inner membrane). •	The outer mitochondrial membrane, which encloses the entire organelle, is 60 to 75 angstroms (Å) thick. It has a protein-to-phospholipid ratio similar to that of the cell membrane. It contains large numbers of integral membrane proteins called porins. •	The intermembrane space is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. •	The inner mitochondrial membrane contains several type of proteins which perform redox reactions of oxidative phosphorylation and help in ATP synthesis and also helps in specific transport of metabolites into and out of mitochondrial matrix. •	The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. •	The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains several copies of mitochondrial DNA(mtDNA) genome.

MITOCHONDRIAL DNA Mitochondria contain their own genome known as mtDNA. The human mitochondrial genome is a circular DNA molecule of about 16 kilobases. In humans, the 16,569 base pairs of mitochondrial DNA encode for only 37 genes. The two strands of mtDNA are differentiated by their nucleotide content, with a guanine-rich strand referred to as the heavy strand (or H-strand) and a cytosine-rich strand referred to as the light strand (or L-strand). It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for rRNA. One mitochondrion can contain two to ten copies of its DNA. Most mitochondrial genomes are circular, although exceptions have been reported. In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such as that of yeast and protists. Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive threads inside mitochondria.

MITOCHONDRIAL DNA INHERITANCE In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). In humans, during sexual reproduction mitochondria are normally inherited exclusively from the mother. The mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. So due to this, single parent (uniparental inheritance) pattern of mtDNA takes place. Two hypothesis have been proposed to explain the mechanism underlying the maternal inheritance of mtDNA. SIMPLE DILUTION MODEL According to the “simple dilution model,” the paternal mtDNA, which is present at a much lower copy number, is simply diluted away by the excess of oocyte mtDNA and consequently it is hardly detectable in the offspring. ACTIVE DEGRADATION MODEL According to the “active degradation model,” the paternal mtDNA or mitochondria themselves are thought to be selectively degraded, either before or after fertilization, to actively prevent the transmission of paternal mtDNA to the next generation.

In different species, distinct mechanisms are present to prevent the inheritance of paternal mtDNA. These mechanisms are: - •	Ubiquitin-mediated degradation of paternal mitochondria. •	Autophagy of paternal mitochondrial structures. •	Degradation of paternal mtDNA before and after the fertilization. •	Degradation of paternal mtDNA during spermatogenesis. •	Degradation of mtDNA from one parent after gamete fusion.

•	Ubiquitin-mediated degradation of paternal mitochondria It was observed that the paternal mitochondria that penetrate the egg disappear during early embryogenesis, implying the degradation of the paternal mitochondria themselves. Sutovsky and colleagues further reported that, in the case of rhesus monkeys, cows, and mice, the paternal mitochondria in fertilized eggs are modiﬁed with ubiquitin and disappear between the 4-cell stage and 8-cell stage of preimplantation development. Ubiquitin signals were also detected on the sperm mitochondria in the male reproductive tract, suggesting that the sperm mitochondria are already tagged by ubiquitin for selective degradation well ahead of fertilization. An inner mitochondrial membrane protein, prohibitin, has been identiﬁed as a potential target for the ubiquitination of sperm mitochondria. It is quite reasonable that the ubiquitination of sperm mitochondria leads to their selective degradation. After fertilization, ubiquitinated paternal mitochondria seem to be degraded by proteasomes and/or lysosomes. •	Autophagy of paternal mitochondrial structures C. elegans is an amenable system for the genetic analyses of internal fertilization and early embryogenesis. C. elegans has 2 sexes, the hermaphrodite sex, which can self-fertilize. When hermaphrodites are crossed with males, the male's sperm are preferentially used for fertilization. Unlike mammalian sperm, C. elegans sperm does not have a ﬂagellum with the midpiece and tail structures. However, it contains 50–70 mitochondria with a characteristic granular morphology around the nucleus in the cell body. C. elegans, sperm-derived paternal mitochondria enter the oocyte cytoplasm together with the other sperm components upon fertilization. Then, the paternal mitochondria gradually disappear by the 16-cell stage and are hardly detectable in later-stage embryos. Recently, it is found that clearance of the paternal mitochondria in early embryos is mediated by autophagy. Autophagy is a mechanism in which autophagosomal membranes sequester cytosolic components (proteins and organelles) and target their contents to lysosomes for degradation. So Immediately after fertilization, autophagosomes, visualized by LGG-1 and LGG-2 staining, were found to form around the penetrated sperm components and to sequester the paternal mitochondria. Paternal mitochondria engulfed by autophagosomes were then delivered to lysosomes for degradation during early embryogenesis. When autophagy-related genes such as LGG-1 were knocked out or knocked down, paternal mitochondria and their genomes were found to persist in late-stage embryos and even in larvae. Thus, the autophagic degradation of paternal mitochondria is a mechanism for the prevention of paternal mtDNA.

Figure 3. Different mechanisms of degradation of paternal mitochondria •	Degradation of paternal mtDNA before and after the fertilization The maternal inheritance of mtDNA has been observed in fish and in insects. In a small fish Oryzias latipes, the elimination of the paternal mtDNA from the egg cytoplasm is achieved through 2 steps. First the no. of mtDNA nucleoids (structure containing DNA and associated protein) gradually decreases during spermatogenesis. About 50mtDNA nucleoids exist in the cytoplasm at the stage of round spermatid, but the number of mtDNA decrease to about 10 in mature sperm. After fertilization, the complete digestion of paternal mtDNA takes place before the destruction of the paternal mitochondrial structure. The nuclease responsible for this digestion has not yet been identified. •	Degradation of paternal mtDNA during spermatogenesis In Drosophila melanogaster, mtDNA is maternally inherited as well. Recently, the fate of paternal mtDNA in D. melanogaster was analyzed. Spermatid undergo a physical transformation as they mature during spermatogenesis. In spermatids at the onion stage, mtDNA is detected in the nebenkern, a spherical aggregation of mitochondria. During spermatid tail formation, mitochondria in the nebenkern fuse with each other to form 2 long mitochondria that elongates next to the extending microtubular axoneme. Many mtDNA nucleoids are first detected in the in the elongating mitochondria, but they gradually disappear from the basal nuclear end to the apical end of the tail during the late elongation stage. Paternal mtDNA seems to be almost completely degraded in mature sperm. Endonuclease G (Endo G) is likely to be one of the key enzymes responsible for the degradation of mtDNA during sperm elongation. In the EndoG mutant fly, the degradation of mtDNA nucleoids in the apical tail is significantly delayed. Interestingly there is a second mechanism to remove mtDNA from the mature sperm. During spermatid individualization, actin containing structures called investment cones move along the axoneme and sweep extraneous cytoplasm into a waste bag. Even in the EndoG mutants, the remaining mtDNA nucleoids are accumulated in the waste bag by the investment cones and eliminated from mature sperm. These elaborate mechanisms for the elimination of paternal mtDNA during spermatogenesis ensure that paternal mtDNA is not transmitted to the offspring. •	Degradation of mtDNA from one parent after gamete fusion Uniparental inheritance of mtDNA is also observed in the true slime mold, Physarum polycephalum, the gametes of which are of uniform size. In this organism, a haploid myxamoeba has more than 13 mating types and mates between different mating types to form diploid zygotes. In 39 of 60 crosses among these haploids, uniparental inheritance of mtDNA was confirmed. In such zygotes, mtDNA nucleoids in mitochondria from only 1 parent are selectively degraded about 3hr after cell fusion. The mitochondrial structures that lose their mtDNA are finally eliminated from the zygote cytoplasm 60hr after mating, by an unknown mechanism. Two type of nuclease activities, Mn2+ dependent and ca2+ dependent nuclease, have been identified as candidates for selective digestion of mtDNA in zygotes, although these nucleases have not yet been identified molecularity. Interestingly, the biparental inheritance of mtDNA was observed in zygotes that result from 21 of the 60 crosses and correlates with a reduction of mtDNA digestion mechanism for the uniparental inheritance of mtDNA might have involved from such unicellular organism.

PATERNAL MITOCHONDRIAL INHERITANCE In genetics, paternal mtDNA inheritance refer to the incidence of mitochondrial DNA(mtDNA) being passed from a father to his offspring. Paternal mtDNA inheritance is observed in a small proportion of species. Very small amounts of paternally inherited mtDNA have been detected in humans in rare cases. Advanced gene-sequencing techniques allowed researchers to identify 17 people who had some paternal mitochondrial DNA, which is normally obliterated early in the fertilization process. CAUSE OF PATERNAL MITOCHONDRIAL INHERITANCE The studies show that the paternal mtDNA inheritance identified in some humans is due to mutation in a nuclear gene that function in paternal mitochondrial elimination.

EVIDENCES OF PATERNAL MITOCHONDRIAL INHERITANCE Mammalian mitochondrial DNA(mtDNA)is thought to be strictly maternally inherited. Sperm mitochondria disappear in early embryogenesis by selective destruction, inactivation or simple dilution by the vast surplus of oocyte mitochondria. Very small amounts of paternally inherited mtDNA have been detected by the polymerase chain reaction. CASE REPORT I Taosheng Huang, a pediatrician and medical geneticist who heads the Mitochondrial Diseases Program at the Cincinnati Children’s Hospital Medical Center, stumbled upon the first individual with mtDNA from both his parents by accident. The patient, a four-year-old boy who had some symptoms of a mitochondrial disorder, including fatigue and exercise intolerance, had come to be evaluated by Huang. The doctor sent his blood sample to the hospital’s diagnostic lab for mtDNA sequencing. The results showed that the boy appeared to have two populations of mitochondrial genomes, both at a relatively high level. “My first instinct was that this was a mistake—even though I’ve never, in six years, seen our diagnostics lab make a mistake like this,” says Huang. He asked the patient to come back, drew a fresh blood sample himself, then sent the blood to the diagnostics lab, an in-house research lab, and an independent laboratory for sequencing. “We saw the same result come back from all three labs. That’s when I said, ‘Ok, this must be real.’” Family members submitted samples for sequencing, and the mitochondrial genomes of the boy’s siblings, parents, and grandparents revealed that both the patient’s mother and grandmother had a similar bi-parental inheritance pattern of their mtDNA. Huang and his colleagues then went back to their patient database and identified another family that exhibited the same phenomenon, and finally a third family who was evaluated at the Mayo Clinic and whose samples were then sequenced at the Baylor College of Medicine in Texas. Some children who had mixed mitochondrial genomes appeared to have inherited the mix from their mothers, having none of their father’s mtDNA. For example, the four-year-old boy didn’t have both parents’ mtDNA, but his mother’s mtDNA and a paternal ancestor’s. In the men with mixed genomes the ability to pass on their mtDNA appeared to be a dominant trait, as they could give their mitochondrial genes to their children. Still, not all of the males with mixed genomes could pass these onto their kids and, according to Huang, men with two populations of bi-parentally inherited mtDNA may just transfer one population onto their offspring. Similarly, mitochondrial genomes of members from three unrelated families, researchers have identified 17 individuals who inherited mtDNA from both parents CASE REPORT II We report the case of a 28-year-old man with mitochondrial myopathy due to a novel 2-bp mtDNA deletion in the ND2 gene (also known as MTND2), which encodes a subunit of the enzyme complex I of the mitochondrial respiratory chain. We determined that the mtDNA harboring the mutation was paternal in origin and accounted for 90 percent of the patient's muscle mtDNA. Schwartz and Vissing describe this patient with exercise intolerance, lactic acidosis after minimal exertion, and ragged-red muscle fibers, a histologic hallmark of mitochondrial myopathy. Sequencing of mtDNA from the patient’s muscle showed a 2-bp deletion resulting in frame-shift mutation in the ND2 gene, which encodes an essential subunit of the mitochondrial NADH dehydrogenase complex. The 2-bp deletion was not present in mtDNA extracted from the patient’s circulating lymphocytes. The analysis of DNA extracted from the patient’s lymphocytes confirmed the expected transmission of mtDNA from his mother. The 2-bp deletion causing disease occurred on the background of mtDNA derived from the father. Thus showing biparental inheritance of mtDNA.

ROLE OF mtDNA IN EVOLUTION17:34, 8 March 2019 (UTC)17:34, 8 March 2019 (UTC)17:34, 8 March 2019 (UTC)~ Until a few decades ago, the only possible way of studying the evolution and migration of mankind was realized mostly through the research on skeletal remains. But now with the help of molecular biology, the study of evolution can also be done. DNA is the only biomolecule accumulating a record of life’s evolution on earth. MtDNA recently been found to possess certain characteristics that that make them very useful in tracking evolutionary events. These properties are: High copy number MtDNA is present in high copy number in human cells. The average somatic cell has just 2 copies of any given nuclear gene or DNA segment, but hundreds to thousands of copies of mtDNA. This property, along with extra nuclear, cytoplasmic location of mtDNA, makes it easier to obtain mtDNA for analysis and also make mtDNA the molecule of choice for analyzing ancient DNA and for certain forensic DNA applications. Maternal inheritance Although paternal inheritance of mtDNA occurs in mussels, and has been shown for inter and intraspecific Drosophila, mouse, bird hybrids, for years the strictly the maternal inheritance of human mtDNA was regarded as an unshakable dogma of the field. This uniparental mode of inheritance is one of the great advantage of mtDNA, as it enables researchers to trace related lineages back through time, highlighting the maternal ancestry of a population, without the confounding effect of biparental inheritance and recombination inherent in nuclear DNA. Lack of recombination MtDNA also does not go undergo recombination. Mutation rate The mutation rate of mtDNA is several orders of magnitude higher than that of nuclear genes, with an estimated rate of 0.017×10¯6substituions per site per year for the whole genome excluding the control region.

There are several reasons for which research into mtDNA might be of great importance in tracing recent human migrations and paths of species evolution. Unlike nuclear DNA, this circular molecule is present in our cells not only in one, but in a number of copies (there are usually 100 to 1000 mitochondria in each  eukaryotic   cell), which   enables detection of much lower amount of the sequence   of   interest, especially   that from fossil material. Due to the fact that only an egg contributes its mitochondria to the developing embryo with only rare exceptions, all human mtDNA is inherited maternally. The molecule apparently lacks recombination, which means that all differences between mtDNA sequences result only from fixed changes. The mutation rate in mitochondrial genomes was proven to be several times higher than that of nuclear sequences and may be the result of lack of re-pair mechanisms that slow down the nuclear genome mutation rate and/or the presence of free radicals formed during the phosphorylation  process. Thus, it generates a high level of sequence variation between individuals, accumulated in a relatively short period of time with respect to the common ancestral mtDNA molecule. The  constant   rate   of   evolutionary change may serve as a molecular clock, enabling research into the age of particular lineages and the time of their divergence, as   long   as   the   clock   is “calibrated”, i.e., its rate is known. This is facilitated with help of paleontological and genetic data, which suggest that human and chimpanzee lineages diverged some 5 million years ago. As the mean genetic distance between sequences of both species is 0.17 substitutions  per   site, the   mutation   rate   in mtDNA was estimated to be 1.7 times10-8 substitutions per site per year. This value might be slightly inaccurate in the light of recent findings that push back the time of divergence between hominids and apes– the discovery of Sahelanthropus tchadensis and  Orrorin   tugenensis   which lived 6-7 million years ago and which could be ancestral to both groups. Many   other    methods    of    studying mtDNA recently applied, such as restriction fragment length polymorphism(RFLP) analysis and direct sequencing, enable more precise calculations to be made. A number of techniques, developed in the last few decades have greatly contributed to the methodology used, with the most pronounced ones, such as polymerase chain reaction (PCR) based methods that allowed the copying of even minute amount of the sequence of interest. CONCLUSION Mitochondrial DNA is the small circular chromosome found inside     mitochondria. This mtDNA is transmitted from parents to offspring. MtDNA was thought to be derived exclusively from maternal egg cells i.e. maternal inheritance. But in rare cases paternal inheritance also takes place. Advanced gene-sequencing techniques allowed researchers to identify 17 people who had maternal as well as paternal inheritance. MtDNA has been found to possess certain characteristics that that make them very useful in tracking evolutionary events.

Nk9158 (talk) 17:34, 8 March 2019 (UTC)

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