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
Describe the spectrum by which Mitochondrial cardiomyopathy occurs?
Variable spectrum
Asymptomatic to sudden cardiac death
Mitochondrial cardiomyopathy is typically manifested as what?
But what can occur?
Hypertrophic cardiomyopathy but dilated and left ventricular non-compaction occur
Mitochondrial cardiomyopathy occurs in approximately…
20-40% of children with mitochondrial disease
- 17/101 of children with mitochondrial disease present with cardiomyopathy (Eur Heart J. 2003;24(3):280-288)
- Onset birth to 10 years
- Diagnosis birth to 27 years
- All non-obstructive hypertrophic type
Cardiac anomalies in adults and this is probably under recognized.
In what forms do these occur?
Hypertrophic or dilated
Heart block common in Kearns-Sayre Syndrome
Abnormal mitochondria and COX (CIV) deficiency in endomyocardial biopsy is found in what?
Childhood cardiomyopathy
Cardiac function routinely monitored in patients with mitochondrial disease with what?
Electrocardiography and echocardiography
What patients are excluded for heart transplantation?
Patients with multisystem disease.
What is an example of an experimental treatment options for Mitochondrial DNA depletion syndrome (MDDS) syndrome?
Nucleoside therapy
Treatments available when specific genetic defect is known
True or false
True
Mitochondrial replacement therapy (Three-parent babies) is used for what?
mtDNA mutations
Mitochondrial diseases with cardiac manifestation can be classified into which 6 biochemical pathways/functions?
- Disorders of oxidative phosphorylation (OXPHOS) complex subunits and their assembly factors
- Defects of mitochondrial DNA, RNA, and protein synthesis
- Defects in the substrate-generating upstream reactions of OXPHOS
- Defects in cofactor metabolism
- Defects in mitochondrial homeostasis
- Defects in other mitochondrial pathways
Disorders of oxidative phosphorylation (OXPHOS) complex subunits and their assembly factors involve what?
5 complexes
For all complexes there is one gene linked to cardiomyopathy, although for complex three it is not a main feature
ACAD9- a protein thought to be involved in a substrate metabolism but has shown to be an assembly factor for complex 1, for this gene cardiomyopathy is a main presenting feature of the disorder. One of the very first genes identified with WES
PPA2- function not as well described. Exquisite sensitivity to alcohol manifested in carriers, for some resulting in sudden cardiac death
ACAD9 is one of the most common
Defects of mitochondrial DNA, RNA, and protein synthesis involve what?
Genes encoding proteins required for replication of mitochondrial DNA,RNA and protein synthesis
All can be classed as gene expression
POLG - one of the most common mitochondrial disease genes, usually affecting brain, muscle and liver and cardiomyopathy present.
Defects in the substrate-generating upstream reactions of OXPHOS involve what?
Includes beta-oxidation disorders involved in fatty acid metabolism
Heart highly dependent on fatty acids for ATP synthesis
CPT2- one of the more common causes
Defects in cofactor metabolism involve what?
Involves cofactors for enzyme including vitamins, small metals present in respiratory chain enzyme complexes such as iron
Fredreichs ataxia caused by mutations in frataxin (FXN), sensory ataxia main feature however some patients present with cardiomyopathy
COQ2- one electron carrier in respiratory chain, transferring electrons to complex three and mutations in these genes essentially affect energy transfer in mitochondria
Defects in mitochondrial homeostasis involve what?
Barth syndrome- one of the most common cardiomyopathies, x linked, caused by mutation in Taz
Cardiolipin- major lipid in membranes of mitochondria. If this is absent, issue in maintaining integrity of mitochondrial membranes
What mitochondrial DNA syndromes manifest with cardiomyopathy?
Kearns-Sayre
MELAS
MERRF
NARP/mtDNA-associated LS
What are new genetic causes of mitochondrial cardiomyopathies?
- Genetic diagnosis of mitochondrial cardiomyopathy in kidCMP population- KidCMP are a cohort of children with cardiomyopathy investigated in single centre in Helsinki University Hospital. NGS performed and mutations in genes with mitochondrial functions explain significant amount of total cardiomyopathies (DNAJC19, HADHB, AARS2, MRPL44, PPA2, TAZ, BAG3).
- Nuclear genetic causes of OXPHOS diseases- Many of the new genetic causes linked mitochondrial disease and cardiomyopathy, found to be those in the class of gene expression, mainly because several genes involved in this pathway, hundreds of proteins needed to replicate mitochondrial DNA. Many new disease genes found in mitochondrial ribosome
- Recessive mutations in mitoribosomal subunits cause mitochondrial disorders
- Mitoribosomal subunit disease with cardiomyopathy
- Two studies discovered MRPL2 and MRPL44, Heterogeneity
How do missense mutations in mitochondrial ribosome proteins lead to cardiomyopathy?
- Protein misfolding / instability of mutated subunit
- Destabilisation of the mitochondrial ribosome structure
- Reduced synthesis of 13 mtDNA encoded OXPHOS subunits
There are specific treatments and no cures
True or false
True
Genetic diagnosis leads to what?
Management and genetic counselling
More disease genes to be discovered
Clinical trials of novel therapies
