Mitochondrial Inheritance Flashcards
How many mitochondria are in a cell?
Hundreds
How many copies of mitochondrial DNA are there per mitocondria?
10 copies mtDNA/mitochondria
How many copies of mitochondrial DNA are there per cell?
100-1000 copies/cell
How many copies of mitochondrial DNA are there in a mature oocyte?
100,000 copies mtDNA/cell
OXPHOS (Oxidative Phosphorylation) is central to these 3 major funtions of mitochondria
- Production of energy
- Generation of reactive oxygen species (lack may lead to cell death)
- Integration of apoptosis signaling (lack of which may lead to premature cell death)
What features make up the physical structure of mitochondrial DNA?
- Double stranded and circular
- 37 genes encoded (totally sequenced)
- Independent transcription of both strands in mitochondria
- No Introns
- More than 100 point mutations and more than -100 rearrangements associated with disorders
What are the genetic components of the OXPHOS complex subunits?
Complex I (7) Complex II (0) Complex III (1) Complex IV (3) Complex V (2) tRNA genes (22) rRNA genes (2)
mtDNA in parentheses
Note: All complexes have contributions from nDNA and only complex II has no contribution from mtDNA
From whom do you receive your mitochondria?
Mother
Does mitochondrial DNA have a higher mutation rate than nuclear DNA?
Yes. (~10X) This increases chance of disease occurance
Where is abnormal expression of mtDNA detected most often and why?
Brain, muscle, heart, kidney, etc.
Seen here because these tissues/organs have high ATP requirements
What is homoplasmy?
Single cell - only one type of mtDNA sequence in the mit population in the cell
Can be either wild type mtDNA or mutant mtDNA
How does mitochondrial genetics relate to the nuclear genome?
Autosomal disorders (AR/AD) similar to mit-genome disorders
Nuclear genes are required for integrity of normal structure and number of mtDNA
What is heteroplasmy?
Single cell with mixed population of mtDNA at a locus - normal mt-genome genotype and mutant mt-genome genotype(s)
Is heteroplasmy a type of mosaicism?
No
Are the levels of cellular heteroplasmy the same in all cells?
No can vary from cell to cell and tissue to tissue
What are some requirements for expression of a disease in an individual with heteroplasmy?
Must reach threshold expression
What is the sequence of events for replicative segratation
- Start with one cell with heteroplasmy
- Repeated cell divisions
- Repeated replications of mt genome
- Random drift (different proportion of mt genome, either mutant or normal, go into each daughter cell)
- Percent of abnormal mutant mt in each cell wil generally determine the function of that cell (ie 60-70% of mutant mt genome required for deleterious expression)
What is threshold expression?
The percentage of mutant mtDNA needed in a cell to show the disease
Can both males and females be affected by mitchondrial disorders if their mother has disorders?
Yes, both inherit the mtDNA from their mother
Are all affected individuals homoplasmic?
No, they can be either homoplasmic or be heteroplasmic with enough mutant mtDNA to surpass threshold levels
Are all unaffected individuals heteroplasmic?
No, hey can be either homoplasmic or be heteroplasmic without enough mutant mtDNA leaving them below the threshold level.
What types of mutations are seen in mtDNA?
Point mutations and insertions/deletions
What things do mitochondrial diseases exhibit?
Reduced penetrance, variable expression, and pleiotropy
What is the estimate of people with a mitochondrial disorder?
1/10,000 - 1/20,000
What are some examples of mitochondrial dieseases?
Leber’s Hereditary Optic Neuropathy
Kearn’s Sayre Syndrome
MERRF
MELAS
What is Leber’s associated with?
Optic nerve atrophy
It is usually homoplasmic
How do individuals acquire MERRF and MELAS?
They have a single base change in tRNA genes
What are the goals of treatment for mitochondrial disorders?
Slow progression
Alleviate symptoms
(No cure)
What do some of the general treatments for mitochondrial disorders do?
Prevent acute decompensation, and they provide or replace deficient metabolites
