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Flashcards in Mitochondria Deck (16):

What are the four parts of the mitochondria and what are their characteristics?

Outer mitochondrial membrane: it is permeable to small molecules, impermeable to large molecules and contains signaling receptors (apoptotic)

Intermembrane space: apoptotic proteins (programmed cell death)

Inner mitochondrial membrane: transporter proteins, electron transport chain, ATP synthesizing complex, impermeable to small and large.

Mitochondrial matrix: contain proteins for the citric acid cycle, lipid oxidation, mitochondrial protein synthesis machinery, mitochondrial DNA


What is the theory of how we have mitochondria?

The ancestral eukaryotic cell was anaerobic. As atmospheric oxygen levels increased, this was toxic to the eukaryotic cell. It engulfed an aerobic bacterium which would use the oxygen and reduce the toxic effects of the oxygen. MItochondria would make ATP and the cell would provide it with food stuff. Symbiotic relationship.


How are mitochondrial proteins produced?

The mitochondria contains protein synthesis machinery to produce proteins it needs

The nucleus will produce precursor proteins which will be transported into the mitochondria to be used.

This is undirectional, proteins do not exit to mitochondria.


How does the mitochondria divide? And what distinctive feature results from this?
(what is homoplasmy and heteroplasmy?)

Like a bacterium, it can undergo fission or fusion.

It results in random replicative segregation of mitochondria and mitochondrial DNA.

Homoplasmy is all mitochondrial DNA is the same

Heteroplasmy - mixture of normal and mutated mitochondrial DNA in the same cell.


What is the organization of the human mitochondrial DNA?

They have 2 - 50 copies of mitochondrial DNA in the matrix of each mitochondrion.

Each circular DNA contains 2 rRNA, 22 tRNA, and 13 protein coding sequences.

The 13 protein coding sequences, produce proteins all part of the oxidative phosphorylation complex and are all embedded in the inner membrane.

A mutation in an tRNA can cause defects in multiple complexes of the mitochondria.


Describe mtDNA replication 5 steps

1. the mtDNA replicates independently of the cell.

2. It forms a D-loop, which is a single strand allowing for machinery to bind and replicate, this is where replication and transcription are controlled.

3. mtSSB: single strand binding proteins bind to the D loop

4. Twinkle is the helicase equivalent

5. The DNA polymerase gamma has proofreeding and exonuclease activity but is more prone to error.


Describe mtDNA transcription.

1. Mitochondrial transcription is initiated at promoters by transcription activator TFAM and mitochondrial tf B1 or B2.

TFAM acts almost like a histone, wrapping around the mtDNA protecting it from DNA damage.

the transcript is polycistronic and gives rise to mRNA, rRNA and tRNA.


What are some differences between universal code and mitochondrial code?

The codons have different amino acids than in the universal code. In the mRNA, no 5' UTR, no cap, and has poly A tial but may even form part of the stop codon?


Why does mtDNA have a high mutation rate? (Its mutation rate is 10-20 times greater)

It is close to reactive oxygen species (because of oxidative phosphorylation, if the machinery is not working correctly it will create ROS which may damage DNA)

DNA polymerase gamma which does proofreading is vulnerable to mutations and defects

There are no introns, so if there is a mutation it will likely affect gene expression


Maternal inheritence of DNA

After fertilization, all paternal mitochondria is destroyed.

Therefore an affected male will not pass on the disease to his offspring but a mother will.


What is the bottleneck effect?

The primordial germ cells contain heteroplasmic mtDNA mutations. IN early oogenesis, there is a reduction in the amount of mtDNA present in the oocyte followed by rapid amplification in the mature oocyte.

Each egg will contain different levels of mutated mtDNA but it will depend on the amount of mtDNA in the primary oocyte.

A mother with a higher proportion of mtDNA in the primary oocyte is more likely to produce eggs with a higher proportion of mutant mtDNA and more likely to have affected offspring.


What is the threshold effect?

It is the amount of ATP required for cell survival, depending on the energy demand of the tissues will be higher or lower.

So we won't see the disease phenotype until we pass the threshold and can't make enough ATP.


How does mtDNA change with age?

The number of mtDNA mutations increase (especially deletions) with age due to free radical damage and defective DNA polymerase gamma.

levels of oxidative phosphorylation decline

if levels of ATP synthesis in the cell drop below the threshold, pathological problems result.

So if a person inherits cells with 40% defective mitochondria, they will feel much older than their same aged counterparts.


How is there a clinical spectrum of mtDNA related syndromes?

Heteroplasmy and different thresholds results in tissues being affected differently

It is common to be asymptomatic.


What is the most common symptom for mitochondrial related diseases?

1. lactic acidosis: those lacking mitochondria will upregulate anaerobic respiration (glycolysis) and lactate will accumulate.

2. Massive mitochondrial proliferation to make up for the lack of mitochondria.

3. muscles will have ragged red fibers. This is due to the accumulation of abnormal mitochondria under the muscle fibers to produce a irregular shaped muscle fiber.

Although their are syndromes without ragged red fibers like Leigh syndrome (a syndrome which has multiple sites in the DNA that can be mutated and will result in Leigh)


What diseases and symptoms result from mitochondrial diseases?

Leigh syndrome,

LHON - Leber Hereditary Neuropathy




Diabetes, deafness, myopathy, CNS defects, and cardiac problems.