Mitochondrial Genetics Flashcards
Describe the mitochondrial genome.
- Mitochondrial genome is double stranded, 16.5 kb, typically circular but may be linear in some tissues.
- Codes for 37 genes: 22tRNA, 2rRNA, 13 subunits of ETC.
- Each mitochondrion has 2 - 10 copies of genome.
Describe the tissue distribution of mitochondrial DNA.
Tissues that are more active will have more mitochondria to acomodate increased energy needs. Mitochondria in more active cells will also tend to have more mitochondrial DNA
What are some important differences between nuclear DNA and mitochondrial DNA.
- Mitochondrial DNA does not replicate with the cell cycle
- Mitochondrial DNA has a far higher mutation rate than nuclear DNA
- Mitochondrial DNA is entirely maternally inherited (sperm mito are degraded upon fert.)
Why does mitochondrial DNA have a higher mutation rate than nuclear DNA?
Mitochondria do not have as many repair mechanisms as nuclear DNA. Also, mitoDNA is more exon dense so the mutations are expressed more.
Define “Heteroplasmy”
Presence of both normal and abnormal mitochondria within a cell, tissue or individual. The percentages of normal and abnormal mito may differ among tissues, cells and individuals. The percentage of abnormal mitochondria may be an explanation for the differences in disease manifestations in cells, tissues and individuals.
Define “Homoplasmy”
Every mitochondria in the cell is the same. The mitochondria can be normal or abnormal.
What is the most important role of the mitochondria and where do the substrates for this process primarily come from?
Most important role is production of ATP via OxPhos (conversion of proton gradient to form ATP). The majority of the substrates for OxPhos come from the CAC.
What areas of the body to mitochondrial diseases primarily affect?
Tissues and organs that are most energetically demanding (i.e. brain, muscle, heart…)
How do you screen for mitochondrial disorders?
- Screening labs
1. Plasma/CSF lactate
2. Ketones, acylcarnitities, urine organic acids (metabolic intermediates)
3. Plasma AA such as alanine. Alanine and lactate interconvert but alanine is more reliable because it gives less false positives.
4. Neuroimaging
What are the cofactors required for pyruvate dehydrogenase?
Thyamine, NAD, FAD, CoA, alpha-lipoic acid
Which complex of the ETC does not have a mutation in either the mtDNA or nDNA that can lead to Leigh’s Syndrome?
Complex II. There can be a mutation in flavoprotein subunit A (SDHA)
What is the significance of POLG1 mutation?
POLG1 is a protein involved in replication of the mitochondrial genome. POLG1 mutation is responsible for a wide range of metabolic diseases because it causes depletion of the mitochondrial genome. This results in a patient’s inability to make normal numbers of substrates required for metabolism (i.e. ETC complexes, tRNAs)
List some disorders caused by POLG1 mutations.
- Alpers Syndrome
- Childhood myocerebralhepatopathy
- MEMSA
- ANS
- AR and AD PEO
What is the significance of a thymidine phosphoylase deficiency?
Thymidine phosphorylase is responsible for the breakdown of dTTP, contributing to the relatively even level of dNTPs present for DNA replication. A thymidine phosphorylase deficiency will result in a build up of dTTP which will be incorporated into mtDNA and nDNA during replication. MtDNA does not have as much rep. repair machinery as nDNA so mutations will accumulate over time. Responsible for MNGIE.
What is the significance of pyruvate dehydrogenase deficiency.
Pyruvate dehydrogenase is responsible for converting pyruvate into acetyl CoA for enrtry into the TCA. Deficiency is an X-linked E1mutation and results in a lot of brain malformations as brain development is a very energetically expensive process and w/o the TCA cycle producing intermediates for ETC there is inadequate ATP. Patients also can experience lactic acidosis due to increased levels of pyruvate which is shunted into lactic acid fermentation for energy production.
