Mitochondria diseases 06/12/22 Flashcards
What is inside the mitochondria?
-Outer membrane
-Inner membrane
-Mitochondrial DNA
-Matrix cristae
-Matrix granule
-Ribosome
What is the purpose of the mitochondria?
Power house of the cell.
What are the cyto-nuclear interactions?
Organelle genomes interact with the nuclear genome during growth and development, and this cooperation is a result of the long co-evolution of nuclear and organelle genomes.
This scheme shows all possible directions of interactions in communication between the nucleus, chloroplast and mitochondrion.
Molecular signalling from organelles to the nucleus is called retrograde signalling. Signalling from the nucleus to organelles is called anterograde signalling.
What are cytoplasmic genetics and extrachromosomal inheritance?
The existence of cytoplasmic DNA shapes a different kind of genetics, called cytoplasmic genetics, with specific rules of extrachromosomal inheritance.
1) Uni-parental inheritance
2) Segregation of cytoplasmic organelles (and so their DNA) during cell divisions is random, not precisely controlled. This complicates the correlation of phenotypes with certain changes in cytoplasmic DNA.
3) Heteroplasmy - multiple copies of DNA within each organelle so there is a possibility to have a mix of normal and mutated forms of cytoplasmic DNA in a single organelle or in a cell.
Mutations in cytoplasmic genes could lead to drastic deviations in development, in particular to human diseases, if we are talking about mitochondrial DNA.
What is bi-parental inheritance?
Inheritance of traits from both parents.
What is uni-parental inheritance?
Inheritance of trails from only one parent. Can be maternal or paternal.
What is the size difference between mitochondrial and nuclear genome?
The nuclear genome (3.3x109 bp) is 200,000 times larger in size than the mitochondrial genome (16,569 bp).
What is the summary of the mitochondrial human genome?
A multicopy, circular dsDNA molecule
(16.6 kb in humans). It encodes 13 essential polypeptides of the OXPHOS system and the
necessary RNA machinery (2 rRNAs and 22 tRNAs) for their translation within the organelle. The remaining proteins for
respiratory-chain complexes, and for mtDNA maintenance, are nuclear-encoded.
What are the transmission and mutability
of cytoplasmic genes?
Transmission of cytoplasmic genes, either mitochondrial or chloroplastic, is different in a few aspects from the transmission of nuclear genes. This is a reflection of the differences between the properties of nuclear and mitochondrial genomes. The mutability of cytoplasmic genes is higher than nuclear genes.
What is an example of maternal inheritance?
Maternal inheritance of variegation in reciprocal crosses. Variegation in plants is known as a phenomenon caused by mutations in chloroplast genes that result in producing some cells without chlorophyll.
If a variegated plant is pollinated with pollen of a green plant (the variegated plant is female and the green plant is male) all progenies from seeds of this cross will be variegated.
In the opposite scenario, when a variegated
male plant pollinates a green female plant, all
progenies from seeds will be green. This is
explained by maternal transmission of
chloroplasts and their genes to progenies.
Who is affected by mutated mitochondrial DNA?
Mothers can only pass mitochondrial mutations but not fathers. So if the mother has the mutation all children are affected, if the father has the mutation no children are affected.
What is the mitochondrial mutation rate compared to nuclear mutation rates in different species?
All species have higher mutation rates in mitochondrial DNA than nuclear ones.
Arachnida and insecta have low mutation rates.
Birds and Squamata (reptiles) have a high mutation rate.
Primates are the most mutable.
Why are mutation rates highest in primates?
The reasons for the high mutability of mtDNA could include:
1) Intensive exposure of mitochondria to ROS. 2) Mitochondria might not have such effective repair systems as in the nucleus.
Why is downs-syndrome increased with a women’s age?
The spindle formation during metaphase is an energy-driven process. An adequate ATP supply by mitochondria is essential.
In aged oocytes:
-A higher percentage of disrupted spindle
-A higher percentage of abnormal tubulin placement from the metaphase plate during the second meiotic division
-A higher percentage of chromosome
segregation failure in oocytes from advanced-age women when compared to younger counterparts
Due to an insufficient energy supply by the mitochondria in the oocytes of advanced-age women, the regulatory mechanisms responsible for assembly of the meiotic
the spindle is significantly altered, which leads to a higher prevalence of aneuploidy compared to oocytes of younger women.
What are the changes in mitochondrial numbers during female germ line development (mitochondrial bottleneck)?
The number of mitochondria per cell and
mtDNA number per mitochondrion are
not constant. They are dependent on
many aspects of development and
physiology. It is also dependent on
energy requirement at a certain stages of
development – since mitochondria are
organelles for producing energy in cells.
The maximum amounts of mitochondria per cell are in mature and fertilized ovicells. The numbers of mitochondria are massively reduced in the blastocyst and primordial follicle, and further reduced in oogonia, with further reduction in primary germ cells where their number is about 10 mitochondria per cell. This reduction to a minimum is called a mitochondrial bottleneck.
What is the random sorting of mitochondrial during cell division?
The mitochondrial bottleneck could be defined as a random reduction in the number of certain mitochondrial types. To a large extent, it depends on the rate of mitochondrial replication at a certain stage of development and on the random sorting out
of mitochondria during cell divisions. There are no specialized mechanisms directing
the equal distribution of mitochondria to daughter cells after cell divisions like it happen, for example, in the case of segregation of chromosomes during mitosis and meiosis. Therefore, if a mitochondrion is mutated then the daughter cell will have mutated mitochondria.
Summary of the factors that go towards manifesting mitochondrial diseases?
Mitochondrial DNA mutates from time to time; this is a normal process during
the replication of DNA. Mutations in mtDNA and mitochondrial bottleneck cause heteroplasmy. On the other hand, some
mitochondrial mutations are harmful to the energetics in cells.
Depending on the heteroplasmy levels among the normal (not mutated) DNA, the mutated DNA could reach a certain proportion (threshold) which is enough to cause symptoms of mitochondrial disease. The severity of the disease is dependent on the proportions of normal and mutated copies of DNA. The highest levels of heteroplasmy (with the highest proportions of mutated mtDNA) lead to the most severe pathological phenotypes. The lowest heteroplasmy levels determine mild phenotype or no phenotype at all. Even so, in this case, female individuals with low amounts of mutated mtDNA are still carriers for the disease, which could be expressed in future generations from such females.
What is mitocondrial fisson and fussion?
Changes within mitochondria are achieved by two core processes - mitochondrial fusion and fission.
-Fusion is joining two mitochondria to make one.
-Fission is the process of splitting one into two.
During these processes the content of mtDNA
per mitochondrion could be changed. For example, in plants fusions of different mitochondria combined experimentally lead to the recombination of mtDNA. In humans,
mtDNA recombination is a very rare event.
How many mutations are associated with mitochondrial disease?
Around 150.
What are 5 examples of mitochondrial disease?
Kaerns-Sayre syndrome - ophthalmoplegia, pigmentary retinitis, often deafness, cerebellar ataxia, and heart block. Heteroplasmic, sporadic, deletion.
LHON – leber hereditary optic neuropathy.
Heteroplasmic or homoplasmic, maternal, single nucleotide polymorphisms.
MELAS – mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Heteroplasmic, maternal, single nucleotide polymorphisms.
MERRF – myoclonic epilepsy and ragged red fiber disease. Heteroplasmic or homoplasmic, maternal, single nucleotide polymorphisms.
Leigh syndrome – loss of mental and movement abilities (death within 2-3 years due to respiratory failure). Heteroplasmic or homoplasmic, sporadic, single nucleotide polymorphisms.
Why are mitochondrial diseases called syndromes?
Very often diseases manifest complex sets of multiple symptoms, so they are called syndromes rather than diseases.
How are mitochondrial diseases diagnosed?
For diagnosis of mitochondrial diseases,
people often use histochemical analysis of
enzymatic activities associated with
mitochondria. Cells are analyzed for the activity of cytochrome c oxidase (COX). COX-positive cells are brown and COX-deficient cells are blue.
What are the guidelines for the recognition of mitochondrial DNA disease?
*Maternal inheritance
* Recognition of classic syndromes
* Recognition of characteristic clinical features. For example, biventricular cardiac hypertrophy
* Involvement of many organ systems. For example, diabetes and deafness
* Specific combinations of symptoms. For example, strokes and migraine, seizures and ataxia
* Abnormal clinical or laboratory investigations. For example, lactic acidaemia in children, characteristic magnetic-resonance-imaging findings, abnormal muscle biopsy that is associated with RAGGED-RED FIBRES, or cytochrome c oxidase-deficient fibers.
How is molecular analysis used in mitochondrial disease diagnosis?
Molecular analyses of mtDNA in patients with different mitochondrial diseases discover more and more genetic changes attributed to
particular diseases.
