Genetics of Mitochondria Flashcards
What are characteristics of mitochondrial diseases?
Monogenic disorders
Phenotypically heterogenous and can affect multiple organ systems, particularly organs that require much energy such as the brain and heart
Can affect adults and children
Can begin at any age
No cure or treatment available
Hallmarks of mitochondrial disease include hydrotropic cardiomyopathy
What are most mitochondrial disorders caused by?
Mutations in genes that either directly affect subunits of oxidated phosphorylation complexes, genes required for synthesis of those complexes, genes involved in metabolism or different substrates which ultimately used to produce ATP
The Mitochondrial genome encode/required to produce what?
Mitochondria are required to produce 13 proteins of OXPHOS. OXPHOS consists of five enzyme complexes CI-CV, in the inner membrane of mitochondria.
The first four complexes are the respiratory chain (RC) complexes (CI-CIV) and CV is the ATP synthase enzyme.
Three of the RC complexes pump protons across the membrane generating electrochemical potential across the membrane. This potential is then utilized by CV to produce ATP. This is known as chemiosmosis and was proposed by Peter Mitchell in the 1960s for which he won a Nobel Prize.
Note that only 13 proteins required for OXPHOS are encoded by mtDNA. More than 100 are needed!
How can mitochondrial disease be inherited?
Primary mtDNA mutations
Nuclear mutations
Autosomal recessive
Autosomal dominant
What are heteroplastic mutations?
More than 1 type of mitchondrial DNA haplotype/variant. E.g., there may be some unaffected indviduals with very low levels of the mutation, with those affected harbouring high levels of mutant. Heteroplasmy is important in understanding level of mutation needed to manifest phenotype.
Inheritance of mutation load is random
What are homoplasmic mutations?
Single mitochondrial DNA variant. Each human cell contains thousands of copies of mtDNA that are usually identical
Females carrying homoplasmic mutation transmit to all children
Most mitochondrial variants are what?
Heteroplasmic
What defects are associated with mitochondrial disease?
Monogenic
> 300 mitochondrial disease genes
Humans produce and consume approximately…
their own body weight in ATP (~65 kg) each day
The heart accounts for 0.5% of body weight but is responsible for what percentage of ATP consumption?
8%
How is mitochondria in the adult heart organised?
Peri-nuclear (PN) mitochondria which are freely arranged in an area adjacent to the nucleus; interfibrillar (IF) mitochondria which are arranged along the myofibrils alongside the sarcomere; subsarcolemmal mitochondria (SSM) which are freely arranged in an area located just beneath the subsarcolemma.
Mitochondria account for approximately 30% ofcardiomyocytes- this is the highest content for any tissue
This demonstrates requirement for high amounts of ATP by cardiac cells for contract and relaxation process
Approximately 90% of ATP generated in cardiac cells is used for contraction and relaxation
Demand for ATP is increased during exercise.
Why is this important?
In mitochondrial diseases as for several mitochondrial disorders, especially myopathies, exercise intolerance is common
If mitochondria are dysfunctional and ATP production is reduced this can lead to what?
Increased oxidative stress and production of reactive oxygen species which are considered to be secondary events occurring within cardiac cells which can contribute to overall pathology that develops in heart when there is an issue with ATP production.
What is cardiomyopathy and what can it lead to?
Cardiomyopathy: Disease of heart muscle that create difficulty for heart to pump blood to rest of body and eventually this can lead to heart failure
Mutations in how many genes cause mitochondrial cardiomyopathy?
> 100 genes
