The role of mitochondria in ageing Flashcards
which energy substrate can be used by mitochondria to generate ATP?
pyruvate
palmitate
glutamine
what does pyruvate dehydrogenase kinases do to pyruvate dehydrogenase complex?
inhibit it by phosphorylation
inhibit pyruvate entry into mitochondria
which electron transport chain complexes generate superoxide radical?
complex I and III
what are the main sources of energy?
carbohydrates - glucose
fats
protein - amino acids
what is the key molecule generated by metabolism?
ATP
mostly generated in mitochondria
mitochondria are
not static, can move
pyruvate entry into mitochondria
pyruvate dehydrogenase complex has to be active which requires pyruvate dehydrogenase kinase to be inactive otherwise they phosphorylate the PD complex and prevent entry of pyruvate into the mitochondria
PDK inhibitors
dichloroacetate
can reduce lactic acid build up as more pyruvate is forced into the mitochondria for oxidation
how many mitochondrial complexes are there?
5
complex I
NADH dehydrogenase
Complex II
succinate dehydrogenase
complex III
cytochrome C oxioreductase
complex IV
cytochrome C oxidase
complex V
ATP synthase
what is the role of the mitochondrial complexes?
generating protons to build up proton gradient in intermembrane space
important complexes in ageing
I and III due to ROS production - superoxide anion
what are the ROS species?
O2 superoxide anion - O2- peroxide - O2^2- hydroxyl radical - OH radical hydroxyl ion - OH-
ROS
not always bad
used to kill pathogens - released from phagocytic cells
pancreatic insulin secretion requires some ROS signalling
how can ROS be detoxified?
enzymatically
ROS scavengers
what enzymes are involved in detoxifying ROS?
superoxide dismutase
catalase
Glutathione peroxidase
superoxide dismutase
superoxide anion –> H2O2
zinc, copper and manganese versions
associated with familial motor neurone disease
Catalase
H2O2 –> H2O
mainly expressed in peroxisomes
glutathione peroxidase
H2O2 + reduced GSH (Glutathione) –> oxidised glutathione (GSSG) + H2O
ROS scavengers
ascorbate
flavonoids
carotenoids
mitochondrial genome
have their own circular DNA containing 37 genes in the mitochondria produces 2 ribosomal RNA 22tRNAs 13 polypeptides
polypeptides produced by mitochondria
components of oxidative phosphorylation complexes
rely on nuclear genome projects because the polypeptides are large
structure of complex I
largest
nuclear and mitochondria DNA encoded subunits
assembly proteins
mutation in complex I
deficiency = Leigh disease/ sundrome
most common cause of mitochondrial deficiency
structure of complex II
succinate dehydrogenase much smaller 4 subunits succinate dehydrogenase a-d A and B = soluble C and D = membrane bound
mutations in complex II
leigh disease
fatal genetic disease within 1 year of diagnosis
cause cancer - shift towards glycolysis if there is a deficiency
complex III structure
only 1 subunit comes from mitochondrial genome, rest from nucleus
mutations of complex III
least common cause of mitochondrial disease
mutations lead to defects in liver, muscle, brain, heart and kidneys - high metabolic rate at rest
structure of complex IV
13 subunits
3 from mitochondria DNA and 10 nuclear
what does complex IV do?
catalyses transfer of electrons to ferrocytochrome C to oxygen to generate water and build proton level up
complex IV deficiency
1 of most important for energy production
complex V role
FoF1 ATP synthase
enzyme channel in mitochondrial membrane
permeable to H+ to flow down concentration gradient
causing a change in shape of ATP synthase, leading to ADP +Pi –> ATP
structure of complex V
large
30 subunits
mitochondrial disease inheritance
fathers with mutant mitochondria do not pass on disease
mothers with only mutant mitochondria will always pass on mutant mitochondria
mothers with some mutant and some normal randomly pass on mutant mitochondria
disease severity is proportional to % of mutant mitochondria someone has
Hutchison-Gilford progeria syndrome
rare genetic disease
accelerated ageing
severe mitochondrial dysfunction
normal ageing
complexes I and III generate ROS which cause oxidative damage to mitochondrial DNA - increasing risk of mutations
mutations accumulate as ageing occurs
causes mitochondria dysfunction and more ROS production
normal ageing allows interaction of ROS with mitochondrial DNA
Harman’s free radical theory of ageing
mitochondrial genes get mutated over time
age-dependent damage to mitochondria
generation of ROS normally cause stress response but if over time a mutation can cause a dysfunctional stress response and oxidative damage occurs
disease
increases generation of ROS and accelerate ageing
which complexes are least likely to be damaged by excess ROS?
complex III
which mitochondrial complex is largest?
complex I
