mitochondrial inheritance (maternal inheritance)

8/3/2019 Mitochondrial Inheritance (Maternal Inheritance)

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MITOCHONDRIAL INHERITANCE Babak Nami MollalouDepartment of Medical Genetics

Selçuk University



Introduction of Mitochondria

• Mitochondria are extremely small (0.5 to10 micrometers in diameter) rice-shapedstructures in the eukaryotic cells.

• Mitochondria are often called the “powerhouses”or "cellular power plants" because they generatemost of the cell's supply of adenosinetriphosrhate (ATP), used as a source of energy.

• Mitochondria are involved in a range of otherprocesses, such as signaling, cellulardifferentiation, cell death, as well as the controlof the cell cycle and cell growth of the cell.



Genome

• Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNAse-sensitive threadinside mitochondria.

• By Ellen Haslbrunner, Hans Tuppy and

Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.



Genome

• mtDNA (16,569 bp) being derived from the circulargenomes of the bacteria that were engulfed by theearly ancestors of today's eukaryotic cells. Thistheory 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 inmammals) are coded for by nuclear DNA, but thegenes for some of them, if not most, are thought tohave originally been of bacterial origin, having since been transferred to the eukaryotic nucleus duringevolution.



Genome

• In total, the mitochondrion hosts about 3000 proteins, but only about 13 of them are coded onthe mitochondrial DNA.

• The proteins involved in the electron transferchain, 2 rRNA subunits and 22 tRNA molecules .

• The number of proteins involved in the electrontransfer chain is much larger than 13, but the

others are coded by the nuclear DNA.



Genome

• Human mtDNA consists of 16,569 nucleotidepairs.

• 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 nuclearDNA, 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”, whichcodes for tryptophan instead.

• “AUA” codes for isoleucine in most organisms but for methionine in vertebrate mitochondrialmRNA.

• 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 UUC2. Leucine (Leu): UUA UUG CUU CUC CUA CUG3. Isoleucine (Ile): AUU AUC4. Methionine (Met): AUA AUG5. Valine (Val): GUU GUC GUA GUG6. Serine (Ser): AGU AGC UCU UCC UCA UCG7. Proline (Pro): CCU CCC CCA CCG8. Threonine (Thr): ACU ACC ACA ACG

9. Alanine (Ala): GCU GCC GCA GCG10. Tyrosine (Tyr): UAU UAC11. Histidine (His): CAU CAC12. Glutamine (Gln): CAA CAG13. Asparagine (Asn): AAU AAC14. Lysine (Lys): AAA AAG

15. Aspartic acid (Asp): GAU GAC16. Glutamic acid (Glu): GAA GAG17. Cysteine (Cys): UGU UGC18. Tryptophan (Trp): UGA UGG19. Arginine (Arg): CGU CGC CGA CGG20. Glycine (Gly): GGU GGC GGA GGGSTOP 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 theinner 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.



Heteroplasmy

• Each cell has hundreds of mitochondria, eachcontaining 2 to 10 copies of mtDNA molecules.

• At cell division, the mitochondria and theirgenomes are randomly distributed to thedaughter cells, a process known as replicativesegregation.

• When a mutation arises in mtDNA, it creates an

intracellular mixture of mutant and normalmolecules, a condition known as heteroplasmy .



Threshold effect



Threshold effect

• Many but not all pathogenic mtDNA mutationsare heteroplasmic.

• The phenotype is normal until a criticalproportion of mutant mtDNA is present within

the tissue and the threshold for genotypeexpression 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 myoclonicepilepsy and ragged-red fibers, the thresholdlevel is about 85% mutated DNA.



Threshold effect

• Different phenotypes associated with the samegenotype are determined mainly by the localizedconcentration and distribution of the mutation in

affected tissues.

• Organs with the highest ATP requirements andthe lowest regenerative capacities, such as the

brain, heart and skeletal muscle, are the mostsensitive to the effects of pathogenic mtDNA mutations.



Age-related somatic mtDNA mutations

• Oxygen free radicals damage mtDNA, causingoxidative modifications of DNA bases, andrearrangements.

• The cumulative accumulation of these somaticmutations during life may cause a bioenergeticdeficit leading to cell death, or apoptosis, andnormal ageing.

• There is much evidence of increased oxidativestress and free radical damage toward defect inmitochondrial energy production in the patients with Alzheimer’s disease and Parkinson’s disease.



Why just from mother?

• In most multicellular organisms, mtDNA isinherited from the mother (maternally inherited).

• Mechanisms for this include simple dilution (anegg contains 100,000 to 1,000,000 mtDNA molecules, whereas a sperm contains only 100 to1000), 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 areusually destroyed by the egg cell afterfertilization.

• Also, most mitochondria are present at the baseof the sperm's tail, which is used for propellingthe 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 paternalmitochondria.



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 don’t

shows autosomal/sex-linked anddominance/recessivity .

• a mitochondrial gene can be wild type or mutant,no heterozygote, no homozygote.

• In a mitochondrial disease, severity of phonotypeis depended to value of total mutations.

• Normally, inheritance probability from mother tochild is 100% and from father to is 0%.



Mitochondrial disease

• The mutation ratio varies from person to person andtissue to tissue (depending on its specific energy,oxygen, and metabolism requirements, and theeffects of the specific mutation).

• Apart from diseases caused by abnormalities inmtDNA, many diseases are suspected to beassociated 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 believedto play a role in the aging process.



Mitochondrial disease

• Mitochondrial diseases are a group of disorderscaused by dysfunctional mitochondria due tomutations 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-onsetdisorders).

• Because cells have multiple mitochondria, differentmitochondria in the same cell can have different variations of the mtDNA. This condition is referredto as heteroplasmy .



KSS: Kearns-Sayre syndrome Inheritance pattern: sporadic

Onset: before age 20Features: This disorder is defined by PEO (usually as the initialsymptom) 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 ordeterioration, delayed sexual maturation and short stature.

Leigh syndrome: subacute necrotizing encephalomyopathy (MILS =maternally inherited Leigh syndrome)

Inheritance pattern: maternal, MendelianOnset: infancy Features: Leigh syndrome causes brain abnormalities that canresult in ataxia, seizures, impaired vision and hearing,developmental delays and altered control over breathing.

It also causes muscle weakness, with prominent effects onswallowing, speech and eye movements.



• MDS: mitochondrial DNA depletionsyndrome

• Inheritance pattern: MendelianOnset: infancy Features: This disorder typically causes muscle weakness and/or liver failure, and more rarely,

brain abnormalities. “Floppiness,” feedingdifficulties, and developmental delays arecommon symptoms; PEO and seizures are lesscommon.



• MELAS: mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes

• Inheritance pattern: maternalOnset: childhood to early adulthoodFeatures: MELAS causes recurrent stroke-likeepisodes in the brain, migraine-like headaches,

vomiting and seizures, and can lead to permanent brain damage. Other common symptoms includePEO, general muscle weakness, exercise intolerance,hearing loss, diabetes and short stature.



• MERRF: myoclonus epilepsy with raggedred fibers

• Inheritance pattern: maternalOnset: late childhood to adolescenceFeatures: The most prominent symptoms are

myoclonus (muscle jerks), seizures, ataxia andmuscle weakness. The disease also can causehearing impairment and short stature.



• MNGIE: mitochondrialneurogastrointestinal encephalomyopathy

• Inheritance pattern: MendelianOnset: usually before age 20Features: This disorder causes PEO, ptosis, limb weakness and gastrointestinal (digestive) problems,

including chronic diarrhea and abdominal pain. Another common symptom is peripheralneuropathy (a malfunction of the nerves that canlead to sensory impairment and muscle weakness).



• NARP: neuropathy, ataxia and retinitispigmentosa

• Inheritance pattern: maternalOnset: infancy to adulthoodFeatures: 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 anemiaand malfunction of the pancreas. Children who

survive the disease usually go on to develop KSS.



• PEO: Progressive externalophthalmoplegia

• Inheritance pattern: maternal, Mendelian,sporadicOnset: Usually in adolescence or early adulthood

Features: As noted above, PEO is often asymptom of mitochondrial disease, butsometimes it stands out as a distinct syndrome.Often, it’s associated with exercise intolerance



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mitochondrial inheritance (maternal inheritance)

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