lecture 28 Flashcards
1
Q
What are mitochondria?
A
- the power plants of the cell
- outer membrane and tightly folded inner membrane
- role in energy generation
fuel + oxygen → energy (ATP)
2
Q
What is our power requirement at rest?
A
- 100kcal/hour = 116W
- O2 consumption 380L/day
- 65kg ATP/day (=$3m worth)
- MIM surface area = 14,000 m^2
- brain: 2% of weight, 20% of energy use
3
Q
What happens if they don’t work?
A
- excerise intolerance at mildest end
- lack of energy in the muscles/poor work capacity
- any symptom, any organ or tissue, any age, any mode of inheritence
hearing
- sensorineural deafness
visual
- death of optic nerve
- cataracts
- retinitis pigmentosa
bone marrow
- all blood cell types
- myelodysplasia
- siderblastic anaemia
- thrombocytopenia
- cyclic neutropenia
heart
- cardiomyopathy
- hypertrophic
- conduction defects
- fibrosis
kidney
- tubules
- glomeruli
- widespread
GIT
- liver failure
- chronic diarrhoea
- villous atrophy
- pseudo-obstruction
- paragangliomas: benign tumours of the carotid body (oxygen sensing organ)
- dysfunction in specific glands e.g. thyroid
- facial dysmorphism
- hypertrichosis (excess hair)
pancreas
- insulin secretion defects
- exocrine dysfunction
4
Q
What is leigh disease?
A
- the most common mitochondrial disease of childhood
- typically healthy until ~6 months
- progressive, episodic neurodegenerative disorder
- motor and or intellectual regression with signs of brainstem dysfunction
- focal symmetric spongiform lesions in CNS
→ demyelination, gliosis, capillary proliferation - see holes lighting up e.g. in basal ganglia
- loss of myelin
- overgrowth of glia
5
Q
What do mitochondria look like?
A
- football shape in hepatocyte
- typical 0.4 x 2.3 µm length
- tightly folded inner membrane
- enourmous SA for proteins to sit on
- football structure from textbooks
- more like a filamentous network that is dynamic
- constantly undergoing fission and fusion
6
Q
What is the distribution of mitochondria in the muscle?
A
- w/i and w/o muscle fibre
- in subsarcolemmal space
- 2% fast muscle fibres
- 8% slow muscle fibres
- 20% liver
7
Q
What is the endosymbiont hypothesis?
A
- primitive aerobic bacterium phagocytosed by a fermentative eukaryotic cell
→ symbiosis and gradual loss of mtDNA functions - mtDNA circular, lacks histones
- inner membrane bacterial-like
- rRNA is chloramphenical S, emetine R: i.e. ribosomes more like bacterial ribosomes than eukaryotic
8
Q
What is the genetic content of the nucleus?
A
- 23 chromosome pairs
- 20,000 genes
- inherit half from each parent
9
Q
What is the genetic content of mitochondria?
A
- 1 chromosome
- 37 genes
- inherited from mother only
10
Q
How many genes encode mitochondrial proteins?
A
- 37 mtDNA genes
- 1000-1500 genes
- 5-10% of our genes encode mitochondrial proteins
11
Q
WHy are mitochondrial disorders complicated?
A
consider other well known genetic disorders e.g. CF
- 1 protein, 1 gene, 1 common mutation
- 1 type of inheritance (autosomal recessive)
- screened for at birth
mito disorders comprise > 150 different monogenic diseases
adult-onset mito disorders
- ~70% maternally inherited mtDNA mutations
- autosomal dominant, sporadic, autosomal recessive
childhood-onset mito disorders
- ~30% maternally inherited mtDNA mutations
- mostly autosomal recessive
- some sporadic, X-linked, autosomal dominant
12
Q
What is the mitochondrial DNA?
A
- double stranded circle
- 16 569 base pairs
- 13 protein-coding genes
- 22 tRNA genes
- 2 rRNA genes
- genes in the mtDNA can’t be read properly by the cytosolic machiner
- chock full of genes
- some overlapping
- heavy strand
- no introns
- interspersed with tRNA
- 7 of the 44 subunits of complex I
- complex III and IV, 1 and 3 respectively
- complex V has a couple of subunits
13
Q
What is the mtDNA morbidity map?
A
- pathogenic point mutations found in 35 of 37 mtDNA genes
MELAS: mito encephalomyopathy, lactic acidosis and stroke-like episodes (typically kids at puberty collapsing/constant seizures) - 80% of the time caused a mutation in the teran A leucine gene
- bunch of other genes in which mutations can cause the same condition
- allelic heterogeneity
LHON: leber’s hereditary optic neuropathy - typically characterised by sudden onset of blindness
- most often caused by mutation in ND4 subunit gene, subunit of complex I, 50% of the time
- mutations in several other genes can cause same presentation
not just one gene causing one clinicical presentation, and not just one clinical presentation being caused by one clinical presentation
14
Q
What are unique features of mtDNA?
A
- maternal inheritance
- mtDNA genes are identical
- nucluear gene gene alleles only 1/256th of great^6 grandmother
- haplogroup K - 16,000 ybp, northern europe
- haplogroup U - 40000 yp, south central asia
- multiple copies (2 to 10/mito and 50, 200,000/cell)
- high mutation rate (~10-fold higher than nucleus)
- used to track female populations around the world
- mt haplogroups used in tracking human migration and in forensics
- heteroplasmy
→ co-existence of mutant and wildtype mtDNA - threshold effect
→ minimum critical proportion of mutant mtDNAs needed for each tissue to become dysfunctional - mtDNA bottleneck
→ in early oogenesis, a small number of genomes are “selected” to repopulate the oocyte, allowing rapid shifts in heterplasmy (resets the biological clock?)
→ mitochondrial numbers decrease and then increase, most of the time you’d clean out the mutant - tissue specific segregation/selection
→ variation b/w tissues because amount of a mutation has increased in one cell lineage and not others in embryogenesis, or more oftenly selection for or against mutation
15
Q
Why is there maternal inheritance ?
A
- in ovum there are 200,000 mitochondira
- sperm 50mt DNA
- in midpiece of sperm
- paternal mitochondria are tagged with ubiquitin
- one documented incidence of paternally inherited mitochondrial disease: exception that proves the rule
