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Babak Nami Mollalou

Department of Medical Genetics Seluk University

Introduction of Mitochondria
Mitochondria are extremely small (0.5 to 10 micrometers in diameter) rice-shaped structures in the eukaryotic cells. Mitochondria are often called the powerhouses or "cellular power plants" because they generate most of the cell's supply of adenosine triphosrhate (ATP), used as a source of energy. Mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth of the cell.

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNAse-sensitive thread inside mitochondria. By Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.

mtDNA (16,569 bp) being derived from the circular genomes of the bacteria that were engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. Each mitochondrion is estimated to contain 2-10 mtDNA copies. In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 3000 different types in mammals) are coded for by nuclear DNA, but the genes for some of them, if not most, are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.

In total, the mitochondrion hosts about 3000 proteins, but only about 13 of them are coded on the mitochondrial DNA. The proteins involved in the electron transfer chain, 2 rRNA subunits and 22 tRNA molecules . The number of proteins involved in the electron transfer chain is much larger than 13, but the others are coded by the nuclear DNA.

Human mtDNA consists of 16,569 nucleotide pairs. The entire human mitochondrial DNA molecule has been mapped. The rate of mutation in mtDNA is calculated to be about ten times greater than that of nuclear DNA, possibly due to a paucity of DNA repair mechanisms.

Genetic code variants

For most organisms the stop codons are UAA, UAG, and UGA. In vertebrate mitochondria AGA and AGG are also stop codons, but not UGA, which codes for tryptophan instead. AUA codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA. So mitochondrial ribosome is distinct too.

Genetic code variants

AUA: methionine (isoleucine in nuclear DNA) AGA: terminator (arginine in nuclear DNA) AGG: terminator (arginine in nuclear DNA) UGA: tryptophan (termination in nuclear DNA)

1. Phenylalanine (Phe):UUU UUC 2. Leucine (Leu): UUA UUG CUU CUC CUA CUG 3. Isoleucine (Ile): AUU AUC 4. Methionine (Met): AUA AUG 5. Valine (Val): GUU GUC GUA GUG 6. Serine (Ser): AGU AGC UCU UCC UCA UCG 7. Proline (Pro): CCU CCC CCA CCG 8. Threonine (Thr): ACU ACC ACA ACG 9. Alanine (Ala): GCU GCC GCA GCG 10. Tyrosine (Tyr): UAU UAC 11. Histidine (His): CAU CAC 12. Glutamine (Gln): CAA CAG 13. Asparagine (Asn): AAU AAC 14. Lysine (Lys): AAA AAG 15. Aspartic acid (Asp): GAU GAC 16. Glutamic acid (Glu): GAA GAG 17. Cysteine (Cys): UGU UGC 18. Tryptophan (Trp): UGA UGG 19. Arginine (Arg): CGU CGC CGA CGG 20. Glycine (Gly): GGU GGC GGA GGG STOP Terminator: UAA UAG AGA AGG

High mutation rate

Mitochondria seem to lack an efficient DNA repair system. Protective proteins such as histones are missing and mtDNA is physically associated with the inner mitochondrial membrane, where highly mutagenic oxygen radicals. These unique features are probably the cause of the about 10 to 17 times faster accumulation of polymorphisms in mtDNA than in nuclear DNA.

Each cell has hundreds of mitochondria, each containing 2 to 10 copies of mtDNA molecules. At cell division, the mitochondria and their genomes are randomly distributed to the daughter cells, a process known as replicative segregation. When a mutation arises in mtDNA, it creates an intracellular mixture of mutant and normal molecules, a condition known as heteroplasmy.

Threshold effect

Threshold effect
Many but not all pathogenic mtDNA mutations are heteroplasmic. The phenotype is normal until a critical proportion of mutant mtDNA is present within the tissue and the threshold for genotype expression is exceeded. This threshold varies for different types of mtDNA mutation and is about 60% for deleted mtDNA. For the mutation 8344A>G, which causes the syndrome of myoclonic epilepsy and ragged-red fibers, the threshold level is about 85% mutated DNA.

Threshold effect
Different phenotypes associated with the same genotype are determined mainly by the localized concentration and distribution of the mutation in affected tissues. Organs with the highest ATP requirements and the lowest regenerative capacities, such as the brain, heart and skeletal muscle, are the most sensitive to the effects of pathogenic mtDNA mutations.

Age-related somatic mtDNA mutations

Oxygen free radicals damage mtDNA, causing oxidative modifications of DNA bases, and rearrangements. The cumulative accumulation of these somatic mutations during life may cause a bioenergetic deficit leading to cell death, or apoptosis, and normal ageing. There is much evidence of increased oxidative stress and free radical damage toward defect in mitochondrial energy production in the patients with Alzheimers disease and Parkinsons disease.

Why just from mother?

In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains 100,000 to 1,000,000 mtDNA molecules, whereas a sperm contains only 100 to 1000), degradation of sperm mtDNA in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg.

Why just from mother?

The mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells. Sometimes the tail is lost during fertilization but some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may cause transmission of paternal mitochondria.

Paternal mtDNA transmission

refer to the incidence of mitochondrial DNA (mtDNA) being passed from a father to his offspring.

Mitochondrial inheritance
Traditionally exist hundreds or thousands copy and not two of mitochondrial gene in one cell. There is non-mendelian inheritance , so dont shows autosomal/sex-linked and dominance/recessivity. a mitochondrial gene can be wild type or mutant, no heterozygote, no homozygote. In a mitochondrial disease, severity of phonotype is depended to value of total mutations. Normally, inheritance probability from mother to child is 100% and from father to is 0%.

Mitochondrial disease
The mutation ratio varies from person to person and tissue to tissue (depending on its specific energy, oxygen, and metabolism requirements, and the effects of the specific mutation). Apart from diseases caused by abnormalities in mtDNA, many diseases are suspected to be associated in part by mitochondrial dysfunctions, such as diabetes mellitus, forms of cancer, cardiovascular disease, lactic acidosis, myopathy, osteoporosis, Alzheimer s disease, Parkinsons disease, Male infertility and which are also believed to play a role in the aging process.

Mitochondrial disease
Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria due to mutations in mtDNA. several different mutations may present themselves as the same disease. Some diseases are observable at or even before birth (many causing death) while others do not show themselves until late adulthood (late-onset disorders). Because cells have multiple mitochondria, different mitochondria in the same cell can have different variations of the mtDNA. This condition is referred to as heteroplasmy.

KSS: Kearns-Sayre syndrome Inheritance pattern: sporadic Onset: before age 20 Features: This disorder is defined by PEO (usually as the initial symptom) and pigmentary retinopathy, a salt-and-pepper pigmentation in the retina that can affect vision, but often leaves it intact. Other common symptoms include conduction block (in the heart) and ataxia. Less typical symptoms are mental retardation or deterioration, delayed sexual maturation and short stature. Leigh syndrome: subacute necrotizing encephalomyopathy (MILS = maternally inherited Leigh syndrome) Inheritance pattern: maternal, Mendelian Onset: infancy Features: Leigh syndrome causes brain abnormalities that can result in ataxia, seizures, impaired vision and hearing, developmental delays and altered control over breathing. It also causes muscle weakness, with prominent effects on swallowing, speech and eye movements.

MDS: mitochondrial DNA depletion syndrome Inheritance pattern: Mendelian Onset: infancy Features: This disorder typically causes muscle weakness and/or liver failure, and more rarely, brain abnormalities. Floppiness, feeding difficulties, and developmental delays are common symptoms; PEO and seizures are less common.

MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes Inheritance pattern: maternal Onset: childhood to early adulthood Features: MELAS causes recurrent stroke-like episodes in the brain, migraine-like headaches, vomiting and seizures, and can lead to permanent brain damage. Other common symptoms include PEO, general muscle weakness, exercise intolerance, hearing loss, diabetes and short stature.

MERRF: myoclonus epilepsy with ragged red fibers Inheritance pattern: maternal Onset: late childhood to adolescence Features: The most prominent symptoms are myoclonus (muscle jerks), seizures, ataxia and muscle weakness. The disease also can cause hearing impairment and short stature.

MNGIE: mitochondrial neurogastrointestinal encephalomyopathy Inheritance pattern: Mendelian Onset: usually before age 20 Features: This disorder causes PEO, ptosis, limb weakness and gastrointestinal (digestive) problems, including chronic diarrhea and abdominal pain. Another common symptom is peripheral neuropathy (a malfunction of the nerves that can lead to sensory impairment and muscle weakness).

NARP: neuropathy, ataxia and retinitis pigmentosa Inheritance pattern: maternal Onset: infancy to adulthood Features: NARP causes neuropathy (see above), ataxia and retinitis pigmentosa (degeneration of the retina in the eye, with resulting loss of vision). It also can cause developmental delay, seizures and dement

Pearson syndrome Inheritance pattern: sporadic Onset: infancy Features: This syndrome causes severe anemia and malfunction of the pancreas. Children who survive the disease usually go on to develop KSS.

PEO: Progressive external ophthalmoplegia Inheritance pattern: maternal, Mendelian, sporadic Onset: Usually in adolescence or early adulthood Features: As noted above, PEO is often a symptom of mitochondrial disease, but sometimes it stands out as a distinct syndrome. Often, its associated with exercise intolerance

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