Mitochondria in ageing Flashcards
Which molecules can generate ATP
Pyruvate, palmitate and glutamine
What does PDK1-4 do?
Inhibit PDC
Which complexes generate superoxide radicals?
1 and 3
Pyruvate entry to mitochondria
- Pyruvate dehydrogenase plays key role
- Pyruvate dehydrogenase kinase reduces pyruvate entry
- Dichloroacetate is PDK inhibitor
Main role of complex I
NADH dehydrogenase
Main role of complex 2
Succinate dehydrogenase
Main role of complex 3
Cytochrome C oxidoreductase
Main role of complex 4
Cytochrome C oxidase
Main role of complex 5
ATP synthesis
What do ROS do?
Kill pathogens
Pancreatic insulin secretion requires ROS secretion
What are SODs?
zinc, copper (cytosolic/extracellular) and manganese (mitochondrial)
What are catalases?
Expressed in peroxisomes
What do glutathione peroxidase do?
Use reduced glutathione as a co-factor, producing oxidised glutathione
What are the three ROS scavengers
Ascorbate, flavonoids, carotenoids
Characteristics of mitochondrial genome
- Circular DNA molecule - double stranded
- 16,000 base pairs containing 27 genes
- 2x rRNA
- 22x tRNA
- 13 polypeptides
- Relies on nuclear genome for additional components
Characteristics of complex 1
- Largest mitochondrial complex
- Nuclear and mitochondria DNA encoded
- Complex i deficiency = Leigh disease/syndrome
Characteristics of complex 2
- Succinate dehydrogenase
- 4 sub-units - ABCD
- Heterotrimer
- A and B are soluble
- C and D are membrane bound
- Mutations = Leigh disease (fatal, neurodegenerative, diagnosed within 1 year of life)
- Mutations in B and D lead to tumorigenesis - glycolytic shift
Characteristics of complex 3
- Least common deficiency
- 11 subunits but only 1 from mito genome
- Mutation = defects in liver, muscle, brain, heart and kidneys
Characteristics of complex 4
- Cytochrome C oxidase
- 13 sub-units
- 3 sub-units from mito genome (COX 1,2,3)
- 10 sub-units from nuclear genome
- Catalyses transfer of electrons to ferrocytochrome C to oxygen = H2O production
- COX IV important for energy production
Characteristics of complex 5
- Metabolism has so far generated H+ gradient across membrane
- Used for F0F1 ATP synthase - permeable to H+
- H+ flow down conc grad like wheel over water
- This changes shape of ATP synthase enzyme
- Powers pi + ADP
- 30 sub-units
Mitochondrial inheritance
- Fathers don’t pass on mito DNA
- Mothers will pass on disease in DNA
- Mothers with some mutant and some normal can randomly pass on mutant DNA
- Disease severity is proportional to % mutant DNA
How do mitochondria get damaged as we age?
- Complex 1 and 3 make superoxide radicals
- Leads to oxidative damage to DNA
- Older = more mutations
- Harman’s theory: mitochondrial genes get mutated over time - closer to source of ROS
Which complex is least likely to be damaged by ROS and why?
3 - only 1 sub unit from mito DNA
Which complex has most sub-units?
1
Hutchinson-Gilford Progeria syndrome
Genetic condition looks like premature ageing
Slowed growth, narrow face
