DSA: Genetics Of Mitochondria

Question 1

What is the phenotypic threshold effect?

Answer 1

Phenotypic manifestation of a genetic defect occurs only when a threshold level is exceeded

Question 2

What is the biochemical threshold effect?

Answer 2

Refers to the possibility of inhibiting the activity of the respiratory chain complex (ETC) to a considerable degree without affecting the rate of mitochondrial respiration or ATP synthesis

[more generally refers to threshold existing at the biochemical level]

Question 3

What is the translational threshold effect?

Answer 3

Refers to the idea that various mutations in mitochondrial DNA affect the rate of protein synthesis more significantly after a certain threshold is reached

Question 4

True or false: the same clinical features can be caused by different mutations in mtDNA and, conversely, that the same genetic defect in mtDNA can lead to different clinical manifestations

Answer 4

True

Question 5

LHON is a mtDNA related disease that affects what aspect of the respiratory chain complex?

Answer 5

Complex I

Question 6

MELASis a mtDNA related disease that affects what aspect of the respiratory chain complex(es)?

Answer 6

Complexes I, III, IV

Question 7

MERRF is associated with what mutation?

Answer 7

tRNA for Lysine

Question 8

What is the most common mitochondria DNA disorder, causing subacute loss of central vision in young adults, predominantly men?

Answer 8

LHON = Leber’s hereditary optic neuropathy

Question 9

Which of the primary mitochondrial DNA-related diseases is more commonly due to nuclear DNA mutations than mtDNA mutations, and results in developmental delay, respiratory abnormalities, recurrent vomiting, nystagmus, ataxia, dystonia, and early death?

Answer 9

Leigh’s syndrome

Question 10

Which of the primary mitochondrial DNA-related diseases is a multisystem disorder in which brain, muscle, and the endocrine system are predominantly involved and is often fatal in childhood or young adulthood?

Answer 10

MELAS - Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Question 11

Which of the primary mt diseases presents differently than the others and includes cervical lipomas as well as myoclonus and epilepsy?

Answer 11

MERRF - Myoclonus epilepsy and ragged red fibres

Question 12

What research method is utilized to study genotype-phenotype relationships in mitochondrial diseases?

Answer 12

Mitochondria obtained from patient cells are transferred to cell line lacking mtDNA (rho^0 cells). In this way, it is possible to create transmitochondrial cell lines containing different proportions of mutated mtDNA and study its effect on the respiratory chain complex, respiration, and cell growth

Question 13

Genotype-phenotype studies on mtDNA have shown the existence of a phenotypic threshold effect, which can be characterized by what 2 characteristics?

Answer 13

Low proportion of wild type mtDNA co-existing with mutated mtDNA with a normal phenotype maintained

Small decrease in above proportion below threshold value alters the phenotype

[shown in MERRF and MELAS, so a certain threshold of mutant mtDNA is needed in muscle before phenotype is expressed]

Question 14

According to scientists, the phenotypic threshold value is around ______ for mtDNA deletions, and around ______ for other mtDNA mutations

Answer 14

60%

90%

Question 15

The phenotypic threshold effect is based on a reserve of different macromolecules and can be considered as a protective mechanism against the effects of ___________ mutations

Answer 15

Deleterious

Question 16

Describe transcription of mtDNA

Answer 16

MtDNA consists of circular double stranded DNA. Transcription occurs independently and in opposite directions for each strand of the molecule (heavy and light); results in 3 polycistronic transcripts that are cleaved further to release 13 mRNAs, 22 tRNAs, and 2 rRNAs

Question 17

Describe translation of mtDNA

Answer 17

Occurs at the level of mitoribosomes, and uses specific genetic code to synthesize respiratory chain subunits

Differences in sequences involved in initiation of translation are responsible for different levels of translation that contribute to maintain a stable stoichiometry between ETC complexes

Question 18

Is the biochemical threshold for mtDNA higher in the brain or in the heart?

Answer 18

The heart

Question 19

In summary, the biochemical threshold effect can be explained by what 3 mechanisms?

Answer 19

1. Mobilization of a pool of inactive respiratory chain enzymes
2. Kinetic regulation
3. Network attenuation

Question 20

What mitochondrial diseases result in neuropathy, ataxia, and retinitis pigmentosa due to mutations at the same nucleotide of mtDNA?

Answer 20

NARP and MILS

Question 21

True or false: those born with reversible respiratory chain deficiency that are sustained vigorously during the perinatal period will recover full mitochondrial function spontaneously within 2 years

Answer 21

True

Question 22

KSS is a mtDNA disease defined by the onset before age 20 with ophthalmoplegia, ptosis, pigmentary retinopathy, and possibly complete heart block, elevated protein in CSF, or cerebellar ataxia. What type of mtDNA mutation causes it?

Answer 22

Sporadic deletions in mtDNA

Question 23

__________, or cytoplasmic hybrids, can be assayed for donor mitochondrial function in a standard nuclear background to study mtDNA diseases

Answer 23

Cybrids

Question 24

What are some of the biochemical and morphological features of mitochondrial disease?

Answer 24

Reduced enzymatic function in one of the ETC complexes and resulting decrease in cellular respiration

Increased lactic acid in blood and CSF

OXPhos disease results in ragged red fiber (RRF) reflecting massive proliferation of defective mitochondria

Question 25

A loss of p53 function has what effect on mitochondria?

Answer 25

Glycolysis and TCA are stimulated but ETC is depressed

This is the crabtree effect

Question 26

In what 3 primary ways does mtDNA differ from nDNA?

Answer 26

Maternally inherited

Present in multiple copies per cell (number varies according to energy needs)

Circular

[note that since there are multiple copies, mtDNA diseases follow the law of population genetics)