Mitochondrial myopathies

Question 1

What features of the mitochondrial genetic system resemble those found in prokaryotes?

Answer 1

Circular DNA and 70S ribosomes.

Question 2

What strengthened the theory that mitochondria are the evolutionary descendants of a prokaryote?

Answer 2

The result of an endosymbiotic relationship with ancestral eukaryotic cells early in the history of life on earth.

Question 3

What is the origin of most mitochondria in an embryo?

Answer 3

Most mitochondria in an embryo are derived from the egg.

Question 4

Where are most mitochondria found in a sperm?

Answer 4

Most mitochondria in a sperm are found in the tail.

Question 5

What happens to paternal mitochondria that enter the egg during fertilization?

Answer 5

Any paternal mitochondria that enter the egg are destroyed.

Question 6

What type of inheritance is associated with mitochondria?

Answer 6

Maternal inheritance.

Question 7

How many copies of the genome are typically found in each mitochondrion?

Answer 7

5-10 copies.

Question 8

How many mitochondria does a cell typically have?

Answer 8

2-2000 mitochondria.

Question 9

What is the size of the human mitochondrial genome?

Answer 9

16.5 kilobases (kb).

Question 10

Where are the majority of mitochondrial proteins encoded?

Answer 10

The majority of mitochondrial proteins are encoded by nuclear DNA on cytosolic ribosomes, imported, and then assembled in the mitochondrion.

Question 11

What has happened to many of the genes needed for mitochondrial function?

Answer 11

Many of the genes needed for mitochondrial function have moved from the mitochondrion into the nuclear genome.

Question 12

What does the mitochondrial genome code for?

Answer 12

The mitochondrial genome codes for 13 respiratory chain proteins, 2 rRNA molecules, and 22 tRNA molecules.

Question 13

How does the mitochondrial genetic code differ from the normal universal genetic code?

Answer 13

The mitochondrial genetic code differs from the normal universal genetic code.

Question 14

How does the tRNA structure in mitochondria differ from nuclear-encoded tRNA?

Answer 14

The tRNA structure in mitochondria differs from nuclear-encoded tRNA.

Question 15

What is the major producer of reactive oxygen species (ROS) in the cell?

Answer 15

The respiratory chain.

Question 16

What happens to mitochondrial DNA (mtDNA) with age?

Answer 16

Defects in mtDNA accumulate with age, and mtDNA mutates more rapidly (10-fold) than nuclear DNA.

Question 17

Which DNA is more susceptible to damage by reactive oxygen species (ROS)?

Answer 17

Mitochondrial DNA (mtDNA) suffers the greatest exposure to, and damage by, ROS.

Question 18

Why is mtDNA less effective at correcting mistakes and repairing damage?

Answer 18

mtDNA is less effective at correcting mistakes and repairing mtDNA damage compared to nuclear DNA.

Question 19

What are the major types of reactive oxygen species (ROS) generated in the mitochondrion?

Answer 19

The major types of ROS generated in the mitochondrion are superoxide anion (O2.-), hydroxyl radical (HO.), peroxide ion (O22-), hydrogen peroxide (H2O2), and hypochlorous acid (HOCl).

Question 20

What happens to the efficiency of oxidative phosphorylation with age?

Answer 20

The efficiency of oxidative phosphorylation declines with age, partly due to the accumulation of mutations to mtDNA caused by ROS.

Question 21

Which conditions or diseases are strongly implicated in defects in oxidative phosphorylation?

Answer 21

Defects in oxidative phosphorylation are strongly implicated in Alzheimer’s disease, Parkinson’s disease, and type II diabetes.

Question 22

When do defects in oxidative phosphorylation occur and progress with age?

Answer 22

Defects in oxidative phosphorylation occur later in life and progressively with age, leading to an enrichment in mutated mtDNA, particularly in tissues reliant on oxidative phosphorylation.

Question 23

Are diseases arising from defects in mitochondrial enzymes and systems, such as in the TCA cycle and oxidative phosphorylation, common or rare?

Answer 23

Diseases arising from defects in mitochondrial enzymes and systems are rare.

Question 24

What is the outcome for embryos affected by major defects in mitochondrial enzymes and systems?

Answer 24

Embryos affected by major defects in mitochondrial enzymes and systems rarely survive.

Question 25

How many different mitochondrial diseases are there?

Answer 25

There are over 150 different mitochondrial diseases.

Question 26

What are some common characteristics of mitochondrial diseases?

Answer 26

Mitochondrial diseases often involve the central nervous system (CNS) and musculoskeletal system.

Question 27

What is the cause of a number of human diseases attributed to mutations in mt genes in mtDNA?

Answer 27

Mutations in mitochondrial genes in mtDNA reduce the capacity of cells to produce ATP, leading to a number of human diseases.

Question 28

What are mitochondrial myopathies?

Answer 28

Mitochondrial myopathies are a group of neuromuscular diseases characterized by exercise intolerance or muscle weakness, often occurring before the age of 20.

Question 29

What are some additional symptoms associated with mitochondrial myopathies?

Answer 29

Additional symptoms of mitochondrial myopathies include heart failure/rhythm disturbances, dementia, deafness, blindness, and seizures.

Question 30

Which tissues or cell types are less able to tolerate lowered ATP production?

Answer 30

Tissues and cell types such as neurons, myocytes, skeletal muscle cells, and the β-cells of the pancreas are less able to tolerate lowered ATP production.

Question 31

What factors contribute to the onset of clinical symptoms, phenotypic variability, and variable penetrance of mitochondrial diseases?

Answer 31

The onset of clinical symptoms, phenotypic variability, and variable penetrance of mitochondrial diseases are governed by the heterogeneity of mitochondrial diseases, homoplasmy and heteroplasmy of mtDNA, and the mt genetic bottleneck.

Question 32

What is the threshold effect in mitochondrial diseases?

Answer 32

The threshold effect refers to the concept that a certain threshold of mutant mtDNA must be exceeded before clinical symptoms of mitochondrial diseases manifest.

Question 33

What is the mt genetic bottleneck?

Answer 33

The mt genetic bottleneck refers to the small number of mother’s mitochondria that are randomly selected and go into each early egg cell during embryonic development.

Question 34

What are some examples of defects in mitochondrial transport systems?

Answer 34

Examples of defects in mitochondrial transport systems include Carnitine palmitoyltransferase (CPT I and II) deficiencies, which are associated with mitochondrial myopathies.

Question 35

What are some examples of defects in substrate utilization?

Answer 35

Examples of defects in substrate utilization include Pyruvate dehydrogenase complex (PDC) deficiency and fatty acid oxidation defects.

Question 36

What are some examples of defects in the TCA cycle?

Answer 36

Examples of defects in the TCA cycle include fumarase deficiency and α-ketoglutarate dehydrogenase deficiency.

Question 37

What is Luft’s syndrome?

Answer 37

Luft’s syndrome is a defect of oxidative phosphorylation coupling.

Question 38

What are combined defects of respiratory chain components?

Answer 38

Combined defects of respiratory chain components refer to deficiencies in Complexes I, II, III, IV, or V of the oxidative phosphorylation system.

Question 39

What is LHON (Leber’s hereditary optic neuropathy)?

Answer 39

LHON is a mitochondrial disorder characterized by a single base change in the mt gene ND4, resulting in an Arg to His substitution in the apolypeptide of Complex I. It leads to partial defects in electron transport from NADH to Ubiquinone, insufficient ATP production for the high metabolic demands of neurons, damage to the optic nerve, and ultimately blindness. Another single base change in the mt gene for cyt b in complex III can also produce LHON.

Question 40

What is MERRF syndrome?

Answer 40

MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is a mitochondrial disorder caused by a point mutation in the mt gene encoding a specific tRNA for lysine (tRNALys). This mutation disrupts the synthesis of proteins essential for oxidative phosphorylation (ATP synthesis). In over 80% of MERRF cases, the mutation occurs at position 8344 in the mt genome. Other tRNA genes, such as mt-TK, mt-TL1, mt-TH, and mt-TF, are also involved. Skeletal muscle fibers of MERRF patients show abnormally shaped mitochondria.

Question 41

What are common mutations associated with mitochondrial DNA?

Answer 41

Leber’s hereditary optic neuropathy (LHON) is associated with a single base change in the mt gene ND4 or cyt b. MERRF syndrome is caused by a mutation at position 8344 in the mt genome and mutations in various tRNA genes.

Question 42

What are the consequences of the single base change in the mt gene ND4 in LHON?

Answer 42

The single base change in the mt gene ND4 in LHON leads to an amino acid substitution (Arg to His) in the apolypeptide of Complex I. This results in mitochondrial dysfunction, particularly in the electron transport from NADH to Ubiquinone, causing damage to the optic nerve and leading to blindness.

Question 43

How does the mutation in MERRF syndrome disrupt ATP synthesis?

Answer 43

The mutation in MERRF syndrome, particularly at position 8344 in the mt genome, disrupts the synthesis of proteins essential for oxidative phosphorylation (ATP synthesis). This leads to impaired ATP production and mitochondrial dysfunction.

Question 44

What is the appearance of skeletal muscle fibers in MERRF patients?

Answer 44

Skeletal muscle fibers of MERRF patients have abnormally shaped mitochondria. These abnormal mitochondria contribute to the symptoms and progression of the disease.

Question 45

What is the significance of clumps of defective mitochondria in aerobic skeletal muscle fibers?

Answer 45

Clumps of defective mitochondria in aerobic skeletal muscle fibers, which appear red after staining with Gomori modified Trichrome, are associated with mitochondrial diseases. These clumps are known as “ragged red fibers.”

Question 46

What methods are used for the diagnosis of mitochondrial myopathies?

Answer 46

The diagnosis of mitochondrial myopathies involves a combination of biochemical tests, histology (examination of tissue), and genetic testing. Blood and urine metabolite analysis, particularly lactate levels, can be performed. Muscle biopsies are used to assess the activity of mitochondrial enzymes, rates of oxidative phosphorylation, substrate utilization, and ATP synthesis. Genetic screening is also conducted to identify specific mutations.

Question 47

What are the treatment options for mitochondrial myopathies?

Answer 47

Treatment options for mitochondrial myopathies are limited and primarily focus on supportive care. Occupational and physical therapy may help extend the range of muscle movement. Vitamin therapies such as riboflavin, creatine, CoQ, C, K, and carnitine may improve function for some individuals. However, there are currently no specific treatments available. The development of genetic strategies for manipulating the mt genome is an area of ongoing research.

Question 48

What is the prognosis for mitochondrial myopathies?

Answer 48

The prognosis for mitochondrial myopathies varies and is dependent on the specific type of disease and the patient’s individual metabolism. The prognosis can vary greatly between individuals.

Question 49

What is the IVF strategy designed to replace defective mitochondria inherited from a mother?

Answer 49

The IVF strategy involves merging DNA from two eggs: one from the mother with defective mitochondria and the other from a healthy donor with functioning mitochondria. The malfunctioning mitochondria are replaced by the healthy ones from the donor.

Question 50

When was the UK parliament’s approval for the mitochondrial replacement strategy granted?

Answer 50

The UK parliament approved the mitochondrial replacement strategy in February 2015.

Question 51

When was the first license for mitochondrial replacement approved?

Answer 51

The first license for mitochondrial replacement was approved in March 2017.

Question 52

What is the process of mitochondrial gene replacement at the pronuclear stage?

Answer 52

Mitochondrial gene replacement at the pronuclear stage involves replacing the defective mitochondria inherited from the mother with healthy mitochondria from a donor.

Question 53

What is an alternative strategy for mitochondrial replacement?

Answer 53

An alternative strategy for mitochondrial replacement is maternal spindle transfer.