The Mitochondrial Genome - Week 6 Flashcards
The mitochondria produces
energy through chemical reactions - breaks down fats and carbohydrates
The mitochondria controls
level of water and other materials in the cell
Common mitochondrial disorder
Mutation in Maternal inherited diabetes and Deafness (MIDD)
The mitochondria is the
powerhouse of the cell
Mitochondria have their own genome. How/why?
o Potentially used to be bacteria before being symbiotic with humans
o They have double membrane like some bacteria, have a genome similar to bacteria – analogous structures
o Probably a different species then they became integrated in cells
o Control lots of enzymatic reactions and different levels of water within the cell
Synthesis processes –
oxidative phosphorylation (ending up with ATP – essential for various enzymatic throughout the cell)
How to visualise mitochondria within the cell
Need GFP (green fluorescent protein) to see mitochondria cells - hundreds of mitochondria in each cell
• Reactions that occur on the membrane surface of mitochondria potentially leading to
the degeneration of ATP – used for many downstream enzyme catalysis and other processes
Many pathogenic mutations are
heteroplasmic (2 or more mitochondrial DNA types)
who do you inherit mitochondria from?
mother
when do you use the term heteroplasmic?
• A new term used when talking about variants and mutations in mitochondria disorders often use the term heteroplasmic
Definition of heteroplasmic
because of the hundreds of different mitochondria in the cell it’s possible that a mutation/variance only occurs in a small subset of the mitochondria, so you could end up with 2 or more different types of mitochondrial DNA
homoplasmy
• If all the mitochondria are wild type or all are mutant
Heteroplasmy
• If two or more mitochondrial DNA types
The idea of heteroplasmy leads to a phenomonen called
maternal bottleneck
Maternal bottleneck explains why mitochondrial disorders are
so variable in their expression (differ massively even within families)
- An example situation - 20% of mother’s mitochondria has mutated so mother has
no symptoms or mild symptoms
- When the early egg cell she produces come together they could have (3 options)
similar number of mutated mitochondria - 20% resulting in child with no disease
mutated mitochondria at around 50% = child with mild disease
mutated mitochondria at around 80% (majority) of the mitochondria might be mutated = child with severe disease
- Even within the same family multiple different
clinical presentations this is related to the fact we only inherit our mitochondria maternally
Human mitochondrial DNA
multicopy - 466-806 nucleoids per cell
Length and diameter of human mitochondrial genome
16,569 bp length and 0.68mM diameter (quite short)
Mitochondrial genes lack
introns - they are single exon genes - so any variants are likely to have a functional effect
Mitochondria are
maternally inherited
Mitochondria were first sequenced in
1981 - NAture
Mutation rate of mitochondria
around 1 per 33 generations (mitochondrial replication - relatively stable over time which helps with forensic analysis
Mitochondria are
heteroplasmic (original and mutated forms co-exist)
organisation of human mitochondrial DNA
Mitochondrial genome is circular, made up of intronless genes = 37 genes
44% GC
heavy (H) strand = G rich and the light (L) strand = C rich
28 genes have H as sense strand, 9 genes have L as sense strand
24 genes encode mature RNA
13 genes encode enzymes involved in oxidative phosphoyraltion
how many genes in mitochondria
37
heavy strands of mitochondria are
G rich
Light strands of mitochondria are
C rich
28 genes have
H as sense strand
9 genes have
L as sense strand
how many genes encode mature RNA
24
how many genes encode enzymes involved in oxidative phosphorylation
13
Difference between nuclear DNA and mitochondrial DNA
that the amino acid code in Mitochondrial DNA is slightly different i.e. UGA in universal DNA would code for a stop codon whereas in mitochondrial DNA this codes for tryptophan etc.
Mitochondrial DNA variants causes
Mitochondrial encephalomyopathies
Mitochondrial encephalomyopathies
• Mutations in every 20-50,000 individuals
• Clinical heterogeneity due to heteroplasmy (vast differences in presentation) but
• Mostly affects post-mitotic tissues with high oxidative demands like muscle and neuron
o Symptoms you’d see for lots of mitochondrial disorders include chronic weakness, chronic fatigue, muscle fatigue and also neurodegeneration.
Mitochondrial disorders
some mitochondrial disorders are caused by point mutations
point mutations causing mitochondrial disorders MELAS
o MELAS (Mitochondrial encephalomyopathy with lactic acidosis & stroke)
general short stature, deafness and epilepsy
Diabetes mellitus, pigmentary retinopathy and recurrent strokes.
Mutation responsible: A-G transition at nt3243 in mt-tRNALeu(UUR) gene
point mutations causing mitochondrial disorders - diabetes and deafness
o Diabetes and deafness:
1.5% of all NIDDM (Non-insulin-dependent diabetes mellitus) mutation in 12S rRNA gene at nucleotide position 1555
hearing loss induced after contact with aminoglycosides
Leber hereditary optic neuropathy (LHON)
- ophthalmological disorder, presenting mainly in young adult males
- characterized by acute or subacute bilateral optic atrophy resulting in loss of central vision.
- > 90% of affected families have mutations at nucleotides 11778, 3460 or 14484, that encode components of complex I of the respiratory chain (very linked syndrome)
- Highly unusual in that majority of mutations present in the homoplasmic state (all of the mitochondria in the cell has the same variant)
- Also unusual is that incomplete penetrance is seen – individuals with these variants that might be in all of their mitochondria may not get the syndrome
Mitochondrial Eve
- Recent African Origin Model suggests that our species evolved from a small African population that subsequently colonised the whole world
- Coalescence analysis indicates that all mtDNA in modern humans can be traced back to a single female (~100-150,000 years ago)
- Diagram shows the House of Africa Hypothesis – where different mitochondria lineages deviated over time.
