Mitochondrial Disease Flashcards
What is the function of the mitochondria?
- generate ATP via OXPHOS (oxidative phosphorylation)
- buffer Ca2+
- Fe-S cluster biogenesis
- for phosphorylation complexes within the mito
- 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
- release of pro-apoptotic molecules (as membrane
Mitochondrial proteins are encoded by genetic material from 2 different origins. What are these origins?
nuclear DNA which is imported to the mitochondria (1200 proteins)
mtDNA (13 proteins)
Why do diseases affecting mitochondrial function impact heavily on neurological function?
mito makes 65kg ATP per day and 20% is used by the brain
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?
Through NADH and FADH2 (produced from the TCA cycle)
mito membrane potential drive the F1F0-ATP synthase (complex 5) which generates ATP
How many ATP molecules are produced from 1 mol of glucose and how many are produced in each stage of cellular respiration?
38 molecules
- 2 from glycolysis
- 2 from TCA
- 34 OXPHOS
What happens during OXPHOS at complex 1?
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
What happens during OXPHOS at complex 2?
- FADH2 is produced here
- electrons from FADH2 are carried by Fe-S complexes to Q
- when electrons get added to Q it becomes QH2
- no protons are moved at this complex
What happens at comlex 3 during OXPHOS?
- QH2 donates one electron to cytochrome c and one electron to Q
- this produces 2 H+ to cross the membrane and another QH2 molecule
- QH2 donates another 2 electrons:: 1 to cyto c and another to Q
- this produces another 2 H+ to cross the membrane
- total of 4 H+ cross the membrane
What happens at complex 4 during OXPHOS?
- cytochrome c catalyses the transfer of electrons from cytochrome c to O2
- 4 cytochrome c are needed as 4 electrons reduce molecular O2 to H20
What happens at the F1F0 ATP synthase (complex 5) in OXPHOS?
- Protons enter back through the ATP synthase from the intermembrane space.
- 4 H+ pass through for 1ADP to be phosphorylated to ATP
OXPHOS complexes are made from which gene types and mutations of these occur in which gene type?
nDNA and mtDNA
mutations found in all 13 mtDNA proteins
mutations in many different nDNA genes
How is mtDNA inherited and how is the percentage of mutated mito in a cell explained?
maternally inherited
homoplasy= all mito are 100% the same
heteroplasmy = any percentage of diseased mito under 100%
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?
low complex concentration as they are not coming together
these cause OXPHOS deficiencies and disease
What are common symptoms of mitochondrial diseases?
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
How is NADH is oxidised to NAD+ by complex 1 in OXPHOS. How is NADH involved in pathways of cellular respiration?
- glycolysis occurs to turn glucose into pyruvate requiring NAD+ to. NADH
- pyruvate then becomes acetyl CoA by pyruvate dehydrogenase
- acetyl CoA going into TCA cycle which turn NAD+ to NADH carrying electrons to OXPHOS
- NADH oxidised to NAD+ by complex 1
- NAD+ is then recycled to glycolysis
If an OXPHOS defect is present NADH accumulates and leads to lactic acidosis. What is the process which leads to lactic acid build up?
- NADH cannot be oxidized at complex 1
- build up of NADH in mito blocks pyruvate dehydrogenase so acetyl CoA cannot be formed
- This leads to an build up in pyruvate
- pyruvate turns into lactate which oxidises NADH to NAD+ to eliminate the excess NADH
- lactic acid is generated as by product of NADH oxidation
Lactate is produced in normally in very small amounts. Large amounts indicate what?
lactic acidosis
Mitochondrial fatty acid beta-oxidation spiral includes which chemical reactions in order?
- dehydrogenation
- hydration
- dehydrogenation
- thiolysis