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Molecular Basis Of Disease > Mitochondrial Disease > Flashcards

Mitochondrial Disease Flashcards

1
Q

What is the function of the mitochondria?

A
  1. generate ATP via OXPHOS (oxidative phosphorylation)
  2. buffer Ca2+
  3. Fe-S cluster biogenesis
    • for phosphorylation complexes within the mito
  4. involved in cell death
    • release of pro-apoptotic molecules (as membrane
      permeability increases) which induces cytochrome c
      release to form apoptosome
    • SMAC/DIABLO also released inhibiting XIAP allowing
      for caspase 3 activation
    • AIF released from mito to induce nuclear chromatin
      condensation
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2
Q

Mitochondrial proteins are encoded by genetic material from 2 different origins. What are these origins?

A

nuclear DNA which is imported to the mitochondria (1200 proteins)
mtDNA (13 proteins)

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3
Q

Why do diseases affecting mitochondrial function impact heavily on neurological function?

A

mito makes 65kg ATP per day and 20% is used by the brain

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4
Q

OXPHOS occurs in the mitochondrial inner membrane by 5 respiratory chain enzyme complexes (1-5). How is mitochondrial membrane potential generated and how is it involved in ATP synthesis?

A

Through NADH and FADH2 (produced from the TCA cycle)

mito membrane potential drive the F1F0-ATP synthase (complex 5) which generates ATP

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5
Q

How many ATP molecules are produced from 1 mol of glucose and how many are produced in each stage of cellular respiration?

A

38 molecules
- 2 from glycolysis
- 2 from TCA
- 34 OXPHOS

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6
Q

What happens during OXPHOS at complex 1?

A

NADH + H = NAD+
- 2 electrons pass through complex 1 into intra-membrane
space to be carried to Q
-

4H+ pass through the intermembrane space to establish a proton gradient

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7
Q

What happens during OXPHOS at complex 2?

A
  1. FADH2 is produced here
  2. electrons from FADH2 are carried by Fe-S complexes to Q
  3. when electrons get added to Q it becomes QH2
  4. no protons are moved at this complex
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8
Q

What happens at comlex 3 during OXPHOS?

A
  1. QH2 donates one electron to cytochrome c and one electron to Q
  2. this produces 2 H+ to cross the membrane and another QH2 molecule
  3. QH2 donates another 2 electrons:: 1 to cyto c and another to Q
  4. this produces another 2 H+ to cross the membrane
    • total of 4 H+ cross the membrane
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9
Q

What happens at complex 4 during OXPHOS?

A
  1. cytochrome c catalyses the transfer of electrons from cytochrome c to O2
  2. 4 cytochrome c are needed as 4 electrons reduce molecular O2 to H20
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10
Q

What happens at the F1F0 ATP synthase (complex 5) in OXPHOS?

A
  1. Protons enter back through the ATP synthase from the intermembrane space.
  2. 4 H+ pass through for 1ADP to be phosphorylated to ATP
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11
Q

OXPHOS complexes are made from which gene types and mutations of these occur in which gene type?

A

nDNA and mtDNA

mutations found in all 13 mtDNA proteins
mutations in many different nDNA genes

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12
Q

How is mtDNA inherited and how is the percentage of mutated mito in a cell explained?

A

maternally inherited

homoplasy= all mito are 100% the same
heteroplasmy = any percentage of diseased mito under 100%

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13
Q

There have been mutations identified in the OXPHOS structural proteins and in the OXPHOS assembly factors. If mutations are found in the assembly factors what is the consequence?

A

low complex concentration as they are not coming together

these cause OXPHOS deficiencies and disease

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14
Q

What are common symptoms of mitochondrial diseases?

A

encephalopathy
- disease of the brain
neuropathies
- peripheral nerve conditions
stroke-like episodes due to ischemia
- convulsions, visual abnormalities, numbness, hemiplegia,
aphasia
myoclonic epilepsy (seizures)
- uncontrolled muscle contractions or twitching
ataxia
- loss of muscle coordination
dystonia
- sustained muscle contractions (twisting, spasms)
myopathy
deafness + blindness
lactic acidosis

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15
Q

How is NADH is oxidised to NAD+ by complex 1 in OXPHOS. How is NADH involved in pathways of cellular respiration?

A
  1. glycolysis occurs to turn glucose into pyruvate requiring NAD+ to. NADH
  2. pyruvate then becomes acetyl CoA by pyruvate dehydrogenase
  3. acetyl CoA going into TCA cycle which turn NAD+ to NADH carrying electrons to OXPHOS
  4. NADH oxidised to NAD+ by complex 1
  5. NAD+ is then recycled to glycolysis
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16
Q

If an OXPHOS defect is present NADH accumulates and leads to lactic acidosis. What is the process which leads to lactic acid build up?

A
  1. NADH cannot be oxidized at complex 1
  2. build up of NADH in mito blocks pyruvate dehydrogenase so acetyl CoA cannot be formed
  3. This leads to an build up in pyruvate
  4. pyruvate turns into lactate which oxidises NADH to NAD+ to eliminate the excess NADH
  5. lactic acid is generated as by product of NADH oxidation
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17
Q

Lactate is produced in normally in very small amounts. Large amounts indicate what?

A

lactic acidosis

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18
Q

Mitochondrial fatty acid beta-oxidation spiral includes which chemical reactions in order?

A
  1. dehydrogenation
  2. hydration
  3. dehydrogenation
  4. thiolysis
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19
Q

what does mitochondrial fatty acid beta oxidation spiral result in?

A

1 acetyl CoA
2. fatty acyl-CoA (2 less carbons)

20
Q

Why are there many different enzymes involved in mitochondrial fatty acid beta oxidation spiral?

A

enzymes change at different stages depending how long the chains are

21
Q

Deficiencies in the mitochondrial fatty acid beta oxidation spiral (FAO) reduce ketone bodies formation. What is the consequence of this?

A

if FAO is not occurring ketone bodies are not formed from acetyl CoA
- therefore organs like the brian and the heart are not receiving ketone bodies from the liver to create acetyl CoA for their own energy purposes

22
Q

How is the process of normal FAO?

A

during fasting (e.g. sleeping):
1. body metabolises fats which are transported to the liver
2. in the liver it forms acetyl CoA which generates ketone
bodies (e.g. hydroxybutyrate, acetoacetate, acetone)
3. ketone bodies then travel around the bodies and
converted back into acetyl CoA and metabolised back
into TCA cycle

23
Q

What are the common clinical symptoms of FAO deficiencies?

A

hypoketotic hypoglycemia
cardiomyopathy
arrhythmias and conduction disorders
skeletal death and breakdown of muscle (causing kidney damage)

24
Q

Is it more common to have an OXPHOS deficiency or FAO deficiency?

A

OXPHOS as FAO deficiency has a much lower prevalence

25
Q

mitochondrial disease presents with a many symptoms when do these present?

A

present at any age

26
Q

There is a range in severity across mitochondrial disease symptoms. It can be lethal in early childhood or have late onset in adulthood. Why might mito diseases have such a large range?

A

due to heteroplasmy
- for late adult onset they may begin life with low heteroplasmy and once enough mitochondria become diseased the disease will show
- for early childhood they may begin life with homoplasy or high heteroplasmy

27
Q

Why is brain and muscle function usually the most affected by mito diseases?

A

tissues that require large amounts of energy

28
Q

What dies the percentage of heteroplasmy indicate?

A

critical for how disease presents and the severity

29
Q

There is no cure for mito disease but some symptoms can be treated. The mito cocktail is one of the treatments. What kind of substances are included in the mito cocktail?

A

ubiquinone (Co-enzyme Q10)
- electron carrier and antioxidant
L-carnitine
Thiamine (B1)
- B1 is a cofactor for pyruvate dehydrogenase to turn
pyruvate into acetyl CoA
Riboflavin (B2)
- cofactor for complex 1 and 2 on OXPHOS
Folic acid
- associated folate deficiency
other vitamins and minerals

30
Q

Why is L-carnitine needed in mito cocktails?

A
  1. long fatty acids CoA chains get converted to fatty acyl
    carnitine to be transported across the mitochondrial
    membrane
  2. Once crossed it turns back to fatty acid CoA chains so
    FAO can occur

Shorter chains (less than 6 carbons) can passively cross membrane

31
Q

Mitocockatils results have demonstrated that?

A

there is no benefit for treating patients

32
Q

Why is avoiding fasting helpful for mito disease patients?

A

stops the switch to FAO
- in patients with FAO deficiencies no ketone bodies will be
produced from this process

33
Q

If there is an OXPHOS disorder rather than a FAO deficiency. A fat based diet can be beneficial why is this?

A

can rely on fat instead of glucose for energy production

34
Q

Increasing medium chain triglycerides in diet through MCT oil helps patients with what?

A

8-10 carbon length fats

allows for easy transport into the mito through passive diffusion (instead of relying on L-carnitine)

35
Q

A treat for mito diease is Dichloroacetate (DCA). What does this do? why is it not used anymore?

A

activates pyruvate dehydrogenase complex to divert away for lactic acidosis

not used due to toxic side effects

36
Q

Synthetic antioxidant CoQ10 is an emerging therapy for Leber Hereditary Optic Neuropathy (LHON). What kind of mutations in is LHON caused by?

A

mtDNA mutations in complex 1 subunits

37
Q

Increasing mitochondrial biogenesis to generate more mito mass in cells is another emerging therapy. Why may this not work?

A

more mito may produce more ATP for patient but mutations in mtDNA can spread (heteroplasmy) or if a nDNA mutation is causing the mito disease it can still affect new mito being produced

38
Q

Bezafibrate is a drug used to treat hyperlipidemia. Wy is it being trailed for mito disease use?

A

can stimulate mito to metabolise more fats which can be used in an OXPHOS mutation

39
Q

Increasing NAD+ levels in mito patients is another emerging therapy. Through Acipimox another drug to treat hyperlipidemia. Why is this consider a potential avenue to help treat mito disease patients?

A

Increasing NAD+ will help drive glycolysis to form Acetyl-CoA avoiding lactate being formed

40
Q

KH17, Elamipretide and EPI-743 are all emerging drugs to treat mito disease. What are they helping to reduce in patients?

A

toxic ROS

41
Q

What is the process of Mitochondrial Replacement Therapy (MRT)/Three parent IVF?

A
  1. a healthy father pronuclei fertilizes the diseased mothers pro-nuclei and a donor pronuclei
  2. father and the donors pronuclei are removed from the donor sample leaving an egg cell with healthy mitochondria
  3. pronuclei from the mother and father are then placed into the donor egg with healthy mito
42
Q

Can MRT be used for all mitochondrial disease types?

A

No
only used in mtDNA mutation mitochondrial diseases

43
Q

What is a pronuclei?

A

nucleus of sperm or egg during fertilization before the genetic material of sperm and egg fuse

44
Q

What are some of the ethical issues with MRT?

A
  1. designer babies
    • mtDNA does not change physical traits of baby though
  2. Destruction of embryos (donor and father)
  3. Donor rights to child?
45
Q

What are the scientific issues with MRT?

A

mito with mtDNA mutations can be accidently transferred with pronuclei
- this may lead to disease later on in life as heteroplasmy levels can change
- this may lead to mutant mito in stem cell lines which can cause an issue when cells differentiate into different cell lines potentially causing a more severe mito disease

46
Q

What is a method that was studied to help achieve low mtDNA mutant transfer in MRT?

A

using prouclear transplantation (ePNT)
- removing the pronuclei at an earlier stage
and different culture conditions (no sucrose)

these two differences demonstrated lower mtDNA carry over

47
Q

How can MRT be used as a fertility treatment?

A

pronuclei taken from mothers egg and put into a healthier younger donor oocyte
- this has shown some success in the Ukraine and Greece

Molecular Basis Of Disease (17 decks)

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