Mitochondrial Disorders

Question 1

Where does oxidative phosphorylation occur?

Answer 1

Matrix

Question 2

Where is the ETC and where are protons being pumped

Answer 2

ETC is on the inner mitochondrial membrane

Protons are being pumped into the intermembrane space

Question 3

Functions of the mitochondria

Answer 3

• Form ATP by oxidative phosphorylation
• Signaling center of cells
• Regulation of apoptosis
• Major source of reactive oxygen species

Question 4

Most mitochondrial disorders are the result of mutations in ___ genomes

Answer 4

Nuclear genomes -> can be AD, AR, X-linked

(More genes in the nuclear genome support ETC than genes in mitochondrial genome)

Question 5

Which is more efficient - aerobic or anaerobic respiration? Why does aerobic respiration need oxygen?

Answer 5

Aerobic respiration is more efficient (38ATP per glucose vs 2ATP)

Oxygen is the final electron acceptor of the ETC

Question 6

Copies of mtDNA vs nuclear DNA

Answer 6

There are mutliple copies of mtDNA in each mitochondrion and multiple mitochondria per cell; whereas, there’s only one complete copy of nuclear DNA per cell

Question 7

Which contains more noncoding DNA - mtDNA or nuclear DNA?

Answer 7

Nuclear DNA; it’s 93% noncoding DNA

Question 8

structure of mtDNA

Answer 8

Double-stranded closed circle w limited mtDNA repair

Question 9

Replicative segregation

Answer 9

Multiple copies of mtDNA in each mitochondrion replicate and sort randomly among newly synthesized mitochondria, which are in turn distributed randomly between daughter cells

–> a mother can have mild/no symptoms, but can produce egg cells with a lot of abnormal mitochondria (bottle neck)

Question 10

Homoplasmy

Answer 10

A cell contains a pure population of normal mTDNA or a pure population of mtDNA

Question 11

Heteroplasmy

Answer 11

Mixture of mutant and normal mtDNA within a cell

Question 12

If Mom is homoplasmic for a mutation, then

Answer 12

all her children will inherit the mutation

Whereas, children of males carrying a mutation will never get it.

Question 13

If Mom is heteroplasmic for point mutations and duplications, then

Answer 13

she will pass them on to all of her children, but the fraction of mutant mitochondria in the offspring will vary (due to random chance + ho wmany mutants the mom had) –> risk and severity of disease will vary

Question 14

Heterplasmic ___ are generally not inherited

Answer 14

Deletions

Question 15

Why is there a “spectrum o fidsease” among family members in which there is heteroplasmy for a mitochondrial mutation?

Answer 15

The fraction o fmutant mitochondria in different tissues for a heteroplasmic individual can vary tremendously

Question 16

Pleiotropy

Answer 16

Pleiotropy: Disorders where multiple, unrelated organ systems are affected

Ex) One person has cardiac arrhythmia, but someone else with the same disorder in the same or a different pedigree has deafness.

Question 17

Variable expressivity

Answer 17

Differing clinical features or phenotype among individuals with the same gene allele or genotype

Question 18

When to consider mitochondrial disease, since it can affect any organ system with any symptom at any time with any form of inheritance

Answer 18

• Unexplained association of neuromuscular and non-neuromuscular symptoms
• Rapid progression
• Unrelated organs (brain, liver, muscle)

Question 19

Diagnostic tools

Answer 19

No single diagnostic tool - Screening, gene sequencing, muscle biopsy

If there’s no lactic acidosis, may not be mitochondrial disease.

Question 20

Two disorders associated with mutation to nuclear DNA

Answer 20

POLG-related disorders

Leigh syndrome

Question 21

POLG-related disorders

Answer 21

POLG is the DNA polymerase for mtDNA replication, so when this is affected there’s a significant drop in mtDNA in affected tissues –> many overlapping phenotypes

• Mostly AR, but some are AD
• Hypotonia
• Failure to thrive
• Mental retardation
• Seizures
• Regression
• brain, liver, muscle

Question 22

Leigh syndrome can be due to nuclear (80%) or mtDNA mutations (20%) - what is it?

Answer 22

Abnormal lesions in the basal ganglia and midline brainstem caused by mitochondrial deletions.

• Progressive neurological disease
• Psychomotor retardation
• Cerebellar ataxia
• Epilepsy

Question 23

KSS, Pearson syndrome, and LEigh syndrome are all caused by

Answer 23

mitochondrial deletion

Question 24

MERRF and MELAS are both __plasmic and caused by mutations in __ DNA

Answer 24

Heteroplasmic; caused by mutations in mtDNA

Question 25

MELAS

Answer 25

• Myopathy
• Mitochondrial Encephalomyopathy
• Lactic Acidosis
• Stroke-like episodes

May present only as diabetes & deafness or

Weakness, ataxia, headache, seizures, dementia, vomiting, transient hemiparesis

Question 26

MERRF

Answer 26

Myoclonic Epilepsy with Ragged Red Fiber

Myopathy, ataxia, sensorineural deafness, dementia

Question 27

A mitochondrial tRNA mutation is only present in 70% of the muscle cells in a patient. This is called

Answer 27

Heteroplasmy

Question 28

Replicative segregation of mitochondria is a significant consideration only when

Answer 28

The cell undergoing division is heteroplasmic

Question 29

Mutations in different genes can lead to the same phenotype