Mitochondrial myopathies Flashcards
Describe mitochondrial DNA
Closed circular double stranded molecule
What is an endosymbiotic origin?
Eukaryotic cells evolved from prokaryotic cells
Both cell types benefited from this relationship
How many copies of the genome are in each mitochondrion?
5-10
How many kb is the human mitochondrial genome
16.5
How are mitochondrial proteins made?
> 900 different mt proteins are encoded by nDNA on cytosolic ribosomes, imported and then assembled in the mitochondrion
Describe why the mitochondria are inherited from the mother
The embryo essentially derives all its mitochondria from the egg
Most sperm mitochondria are in the tail - not absorbed on fertilisation
Any paternal mitochondria that do enter egg are destroyed
What does the mitochondrial genome code for?
13 of the respiratory chain proteins
2 rRNA
22 tRNA
What is the major producer of reactive oxygen species?
Respiratory chain
Why are ROS dangerous?
Can disrupt function of mitochondria
Mitochondrial genome suffers the greatest exposure and damage to…
ROS
How effective is mitochondrial DNA at correcting mistakes and repairing DNA damage?
Less effective
Describe what happens to defects in mitochondrial DNA over time
Consequently defects in mtDNA accumulate with age and mtDNA mutates more rapidly (x 10-fold ) than nDNA
Give the equation for the full reduction of oxygen
O2 + 4e- —–> H2O
What can also occur in terms of reduction of oxygen?
Partial and subsequent reduction of oxygen generating ROS
Describe the efficiency in OXPHOS
Efficiency declines with age as a result of the accumulation of mutations to mtDNA caused by ROS
OXPHOS enzyme defects strongly implicated in Alzheimer’s/Parkinson’s and type II diabetes
Describe the defects in OXPHOS
Involve tissues most reliant on OXPHOS
Occurs later in life
Progressive with age
Show progressive enrichment in mutated mtDNA’s
Describe some mitochondrial diseases
Diseases arising from defects in mt enzymes and systems e.g. in the TCA cycle and OXPHOS are rare
Major defects are incompatible with life and affected embryos very rarely survive
Nevertheless there are over 150 different mitochondrial diseases and some are linked to mtDNA
Often involve CNS and musculoskeletal system
Why do most mitochondrial diseases affect the CNS and skeletal muscle?
Have highest numbers of mitochondria
Describe mitochondrial myopathies
A number of human diseases are attributed to mutations in mt genes in mtDNA that reduce the capacity of cells to produce ATP
Some tissues / cell types e.g. neurons, myocytes, skeletal muscle cells and the -cells of the pancreas are less able to tolerate lowered ATP production
Group of neuromuscular diseases
Most occur before the age of 20, often beginning with exercise intolerance or muscle weakness
Other symptoms include heart failure / rhythm disturbances, dementia, deafness, blindness and seizures
Onset of clinical symptoms, phenotypic variability, and variable penetrance of mt diseases are governed by:
Homoplasmy and heteroplasmy of mt - threshold effect
Mt genetic bottleneck
Describe the threshold effect
Within a cell you may have normal and mutated mitochondria.
When the cell divides the proportion of mutated to normal may change therefore changes the severity.
Many diseases are caused by mutant mt DNA - a cell is termed heteroplasmic if it has both normal and mutant mt DNA present. Heteroplasmy is the threshold value of expression (varies) and this determines if a disease is manifested.
When the level of mutant mitochondria exceeds a certain threshold, the cell expresses dysfunction
Describe the mitochondrial genetic bottle neck
Randomly selected mitochondria goes into each early egg
Give some examples of mitochondrial myopathies
LHON- Lebers hereditary optic neuropathy
MERRF- myoclonus epilepsy with ragged red fibre
MELAS- mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
KSS- Kearns-Sayre syndrome
Describe Leber’s hereditary optic neuropathy
Single base change in the mt gene ND4, (from Arg to His) in a polypeptide of Complex I
Mitochondria partially defective in e- transport from NADH to UQ
Some ATP produced by e- transport from succinate, but not enough to support the very active metabolism of neurons
Results in damage to the optic nerve and leads to blindness
A single base change in the mt gene for cyt b in complex III also produces LHON
Describe Myoclonus epilepsy with ragged-red fibre
Caused by a point mutation in the mt gene encoding a tRNA specific for lysine (tRNALys)
Disrupts synthesis of proteins essential for oxidative phosphorylation (ATP synthesis)
MERRF syndrome is caused by a mutation at position 8344 in the mt genome in over 80% of cases
Many other genes are involved and include:
mt – TK, mt - TL1, mt – TH, mt – TF
Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
What are ragged red fibres?
Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres (appear red after staining with Gomori modified Trichrome)
Associated with mitochondrial disease
Describe Mitochondrial encephalomyopathy
Mt myopathy affecting primarily the brain and skeletal muscle
mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV (all involved with tRNA)
Symptoms appear in childhood and include: a build up of lactic acid (lactic acidosis), stroke-like episodes with muscle weakness, seizures leading to loss of vision, movement difficulties (incl. involuntary muscle spasms (myoclonus) and dementia
Describe Kearns-Sayre syndrome
Results from a 5kb deletion of the mt genome
Onset before age 20
Affected patients have short stature and often have multiple endocrinopathies including diabetes
Symptoms include dementia & retinitis pigmentosa
Other symptoms include lactic acidosis, heart conduction defects and raised cerebrospinal fluid protein content
What is the prognosis for patients with mitochondrial myopathies
Variable and dependent on the type of disease and the patient’s metabolism (varies greatly between individuals)
Give some examples of the treatments used
Occupational / physical therapy may extend the range of muscle movement. Vitamin therapies such as riboflavin, creatine, CoQ, C, K and carnitine may improve function for some
No specific treatments and attention is now turning to the development of genetic strategies for manipulating the mt genome
How can mitochondrial myopathies be prevented?
IVF strategy designed to replace defective mitochondria inherited from a mother
Strategy involves merging DNA from two fertilised eggs - one from the mother with defective mitochondria, the other from a healthy donor with functioning mitochondria
Malfunctioning mitochondria are replaced by the donor healthy ones
List the two procedures used to prevent mitochondrial myopathies
Mitochondrial gene replacement (pronuclear stage)
Maternal spindle transfer
Describe mitochondrial gene replacement (pronuclear stage)
Patients egg with abnormal mitochondria fertilised with patients sperm
Patients zygote with abnormal mitochondria
Patients pronuclei removed from the zygote and transferred to enucleated egg which has normal mitochondria
Cleaving embryo with maternal and parental DNA and normal mitochondria is transferred back to the mothers uterus
Describe the process of maternal spindle transfer
Unfertilised patients egg with abnormal mitochondria
Spindle and associated chromosomes removed as karyoplast from the patients egg and then fused with the enucleated donor egg
Reconstituted egg is fertilised with the patients sperm
Cleaving embryo with parental DNA and normal mitochondria can be transferred into the uterus
