Mitochondria in Neurodegeneration Flashcards
mitochondria function
Oxidative phosphorylation
Calcium homeostasis
Apoptosis
Fatty acid oxidation
What determines mitochondria function ?
Shape
Motor Neuron Disease
- Adult onset, rapidly progressing, neurodegenerative disease
- Characterised by loss of both upper and lower motor neurons (MN)
- Muscle wasting & paralysis
- Death 2-3yrs from onset
MtDNA in PD
- Possible association with particular haplogroups of mtDNA
- Secondary mtDNA deletion rates increased in post mortem tissue
- Link between function and mtDNA??
- possible target for therapy
Mitochondrial morphological abnormalities
SOD1 gene mutation
Often complexes 2 and 4 identified
Mitophagy in PD
Parkin and PINK1 function in the same pathway- both cause early onset Parkinsons
PINK1 recruits parkin to depolarised mitochondria
parkin interacts with p62 to tag the mitochondria to undergo mitohpagy
PINK1 Acts as a sensor on mito mem but constitutively degraded
Oligomycin
inhibits complex 5 of Resp chain
HD-
• Hyperkinetic choreiform movements
• Pathology in the striatum
• Mutant huntington
• CAG triplet repeat extensions which are pathogenic
• Possible mechanisms include
endocytosis, intra-neuronal trafficking, transcriptional regulation, mitochondrial function
HD post mortem
Post mortem -CII defects prominent
MtDNA changes – reduced in HD
Morphology changes – less fold in the cristae
Changes in peripheral tissues as well
What process do fibroblast used for 95 % of their energy production?
Glycolysis
What energy process do neurons mainly rely on ?
Oxidative Phosphorylation
HD animal models
- Mutant htt and WT htt localise to the OMM
- Ultrastructural changes
- CII defects found only in symptomatic animals – in striatum
- Mthtt reduces O2 consumption – correlates to CAG repeat length
Parkinsons Disease
• Most cases are sporadic
• Familial form due to mutations in several identified genes
autosomal recessive – parkin, PINK1, DJ1
autosomal dominant – α synuclein, LRRK2
• Pathogenesis 3 main pathways
oxidative stress
proteasome dysfunction
mitochondrial dysfunction
• Interplay between environmental
and genetic factors
loss of dopaminergic in SN
Autosomal Recessive
parkin, PINK1, DJ1
Autosomal Dominant
α synuclein, LRRK2
3 Pathways of Pathogenesis
oxidative stress
proteasome dysfunction
mitochondrial dysfunction
toxin induced mitochondrial dysfunction –
Exposure to pesticides/Herbicides - MPTP - Rotenone - Paraquat Toxin can induce systemic But neuron affected are the dopaminergic
Fibroblasts from Parkin patients
Reduction in complex 1
ATP production red when introduced at complex 1
PINK1 models
Massively hyperfused mitochondrial network in fibroblast mutants
PINK1 modes – mitochondrial defects
-PINK1 Mice models don’t show neurodegenerative loss but rat models do
Master regulator TF and HD
PGC-1 Alpha
Reduced in HD – down reg
What does Oxidative Phosphorylation use ?
- Repsiratory chain complexes
- Coenz Q
- Cytochrome C electron acceptor in the chain
Oxidative Phosphorylation
- Redox of NADH+H+ at Complex 1- 4 protons pumped from matrix to inter membrane space
- Redox of FADH2 at complex2 Coenz Q picks up electrons from 1 &2 and takes to comple 3
- Redox of Complex3 4 protons pumps from matrix to intermembrane space. carrier C transports electrons to complex 4
- ATP synthase reaction - pumps protons from intermembrane space to matrix and produces ATP from ADP+ Pi + energy
1,3 and 4 main component
of electrochemical gradient in the mitochondrial membrane which is then used by complex 5
Mitochondrial action
- Constantly undergo fission and fusion events
- Form an elaborate network in some cell types
- Both inner and outer membranes must undergo fission and fusion events
- Mitochondrial morphology correlates with mitochondrial function
Mitochondrial degradation
Autophagy – Bulk
Or Ubiquitin – proteasome selective
Mix of both starts selective but whole organelle degraded by autophagosome
Neurodegenerative Disease
- Increasing prevalence with age
