Mitochondrial myopathies

Question 1

What is the structure of mitochondrial DNA?

Answer 1

• closed circular double stranded molecule
• Human mt genome is 16.5 kb
• 5 -10 copies of the genome in each mitochondrion (a cell has 2 - 2000 mitochondria)
• > 900 different mt proteins are encoded by nDNA, translated on cytosolic ribosomes, imported and then assembled in the mitochondrion

Question 2

What does “ ENDOSYMBIOTIC ORIGIN “ mean?

Answer 2

• Many features (circular DNA / 70S ribosomes) of the mt genetic system resemble those found in prokaryotes
• Strengthened the theory that mitochondria are the evolutionary descendants of a prokaryote
• Result of an endosymbiotic relationship with ancestral eukaryotic cells early in the history of life on earth

Question 3

How does maternal inheritance work?

Answer 3

• 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

Question 4

Answer 4

Question 5

Answer 5

Question 6

What does the mitochondrial genome code for?

Answer 6

•Many of the genes needed for mitochondrial function have moved from the mitochondrion into the nuclear genome over evolutionary time

Question 7

Label the diagram

Answer 7

Question 8

What effect does ageing have on mitochondria?

Answer 8

ØEfficiency declines with age

ØPartly as a result of the accumulation of damage and mutations to mtDNA caused by ROS

Question 9

What conditions are associated with OXPHOS defects?

Answer 9

ØDefects in OXPHOS are strongly implicated in Alzheimer’s/Parkinson’s and type II diabetes

Question 10

What are OXPHOS defects?

Answer 10

• involve tissues most reliant on OXPHOS
• occurs later in life
• progressive with age
• show progressive enrichment in mutated mtDNA’s

Question 11

What are redox reactions?

Answer 11

Reduction-oxidation reactions are essential for cell metabolism

Question 12

Write an equation for the reduction of oxygen

Answer 12

Question 13

Name the reactive oxygen species (ROS)

Answer 13

Superoxide anion (O2.-)

Hydroxyl radical (HO.)

Peroxide ion (O22-)

Hydrogen peroxide (H2O2)

Hypochlorous acid (HOCl)

Question 14

Answer 14

Question 15

How does the efficiency of OXPHOS change with aging?

Answer 15

• Respiratory chain is the major producer of reactive oxygen species (ROS)
• mt genome suffers the greatest exposure to, and damage by, ROS
• mt DNA less effective at correcting mistakes and repairing mt DNA damage

Question 16

What are mitochondrial diseases?

Answer 16

ØDiseases arising from defects in mt enzymes and systems e.g. in the TCA cycle and OXPHOS are rare

Question 17

What is the effects of mitochondrial diseases?

Answer 17

ØMajor defects are incompatible with life and affected embryos very rarely survive

ØNevertheless there are over 150 different mitochondrial diseases and some are linked to mtDNA

Question 18

What are mitochondrial myopathies?

Answer 18

ØMitochondrial diseases often involve CNS and musculoskeletal system (also known as mitochondrial myopathies)

•Group of neuromuscular diseases

Question 19

What are the 5 biochemical classifications of mitochondrial disease?

Answer 19

1. Defects of mitochondrial transport systems

Carnitine palmitoyltransferase (CPT I and II) deficiencies

2. Defects of substrate utilisation

Pyruvate dehydrogenase complex (PDC) deficiency

Fatty acid oxidation defects

3. Defects of TCA cycle

Fumarase deficiency OR a- ketoglutarate dehydrogenase deficiency

4. Defects of OXPHOS coupling

Luft’s syndrome

5. Defects of oxidative phosphorylation

Complex I / II / III / IV / V deficiencies (defects of respiratory chain components)

Question 20

Why are the majority of mitochondrial diseases mitochondrial myopathies?

Answer 20

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 b-cells of the pancreas are less able to tolerate lowered ATP production

Question 22

What are the symptoms of mitochondrial myopathies and when do they arise?

Answer 22

• 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

Question 23

Onset of clinical symptoms, phenotypic variability, and variable penetrance of mt diseases are governed by…

Answer 23

• Homoplasmy and heteroplasmy of mt - threshold effect
• Mt genetic bottleneck

Question 24

What is the threshold effect?

Answer 24

Question 25

What is the mitochodrial genetic bottleneck?

Answer 25

Question 26

Name the Mt myopathies caused by mutations in mtDNA

Answer 26

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

Question 27

What is the genetics of LHON syndrome?

Answer 27

* Single base change in the mt gene ND4, (from Arg to His) in a polypeptide of Complex I * A single base change in the mt gene for cyt b in complex III also produces LHON

Question 28

What causes LHON syndrome?

Answer 28

* Mitochondria partially defective in e- transport from NADH to ubiquinone * Some ATP produced by e- transport from succinate, but not enough to support the very active metabolism of neurons

Question 29

What are the symptoms of LHON syndrome?

Answer 29

•Results in damage to the optic nerve and leads to blindness

Question 30

What are the genetics of MERRF syndrome?

Answer 30

* Caused by a point mutation in the mt gene encoding a tRNA specific for lysine (tRNALys) * 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

Question 31

What causes MERRF syndrome?

Answer 31

* Disrupts synthesis of proteins essential for oxidative phosphorylation (ATP synthesis) * Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria

Question 32

Whats the diagnosis?

Answer 32

MERRF syndrome Ragged red fibres

Question 33

What are ragged red fibres?

Answer 33

Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres (appear red after staining with Gomori modified Trichrome) Associated with mitochondrial disease

Question 34

What are the symptoms of MELAS syndrome?

Answer 34

Mt myopathy affecting primarily the brain and skeletal muscle Symptoms appear in childhood and include: 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

Question 35

What are the genetics of MELAS syndrome?

Answer 35

•mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV (all involved with tRNA)

Question 36

What are the genetics of Kearns-Sayre syndrome (KSS)?

Answer 36

Results from a 5kb deletion of the mt genome

Question 37

What are the symptoms of KSS and when is the onset?

Answer 37

* 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

Question 38

How are mitochondrial mypopathies diagnosed?

Answer 38

•Diagnosis: combination of biochemical tests, histology & genetic testing

Question 39

What is the prognosis of mitochondrial myopathies?

Answer 39

•Prognosis: variable and dependent on the type of disease and the patient's metabolism (varies greatly between individuals

Question 40

What is the treatment for mitochondrial myopathies?

Answer 40

* No specific treatments. Development of genetic strategies for manipulating the mt genome * 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

Question 41

How are mitochondrial myopathies prevented?

Answer 41

* IVF strategy designed to replace defective mitochondria inherited from a mother * Malfunctioning mitochondria are replaced by the donor healthy ones * Strategy involves merging DNA from two eggs - one from the mother with defective mitochondria, the other from a healthy donor with functioning mitochondria * Approved by UK parliament in February 2015 * First licence approved in March 2017

Question 42

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Question 43

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