What is a Mitochondrion

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What is a Mitochondrion?

• A cellular organelle probably of endosymbiotic
  origin that resides in the cytosol of most
  nucleated (eurkaryotic) cells.
• This organelle produces energy by oxidising
  organic acids and fats with oxygen by the process
  of oxidative phosphorylation and generates oxygen
  radicals (reactive oxygen species ROS )as a
  toxic by-product

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Mitochondrial Genetics

• Each cell contains many mitochondria, each of
  which contains multiple copies of 16.5-k-b
  circular DNA molecule
• The mitochondrial genome is subject to a number
  of peculiarities of inheritance

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Mitochondrial Genetics

• Interest in mitochondrial genetics comes mostly
  from
• interest in diseases caused by mutations in mDNA
• interest in human history
• Doug Wallace.(mitochondrial enthusiast)

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The nuclear and Mitochondrial genetic codes are
similar but not identical
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The human nuclear and mitochondrial genomes
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Table continued..
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Oxidative phosphorylation
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The limited autonomy of the mitochondrial genome
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Maternal genetic transmission
An affected woman transmits the trait to all her
children. Affected men (represented by squares do
not pass the trait to any of their offspring
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Mitochondrial inheritance. Sperm mitochondria are
shed before entry of the sperm nucleus. All
mitochondrial in the zygote are contributed by
the egg cell
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Concept of heteroplasmy. Both wild-type and
mutant (gray) mitochondria are included in the
hundreds of mitochondria in a cell. These
mitochondria segregate passively when the cell
divides. This can lead to variation in the
proportion of affected mitochondria in different
tissues or different individuals in a family
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Number of Mitochondria per cell

• Most somatic cells 100-10,000
• Lymphocyte 1000
• Oocytes 100,000
• Sperm few hundred
• No mitochondria in red cells and some terminally
  differentiated skin cells

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Myoblasts were isolated from muscle cells
obtained from an individual with MERRF. They were
fused to make myotubes.Protein production was
normal in htose with about 16 normal
mitochondria
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Some diseases associated with mitochondrial
mutations
MERRF (Myoclonic Epilepsy with Ragged Red Fibres
MELAS (Myopathy,Epilepsy Lactic
acidosis,Stroke-like episodes
LHON (Lebers Hereditary Optic atrophy)
Kearn-Sayre (eye problems,heart block,ataxia ie
loss of coordination
Leigh syndrome(rare severe brain disease in
infancy,also heart problems)
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Michael presented with muscle problems,
epilepsy,lack of progress at school,difficulty
with vision and hearing. Diagnosed as MERRF aged
12 after muscle biopsy.At postition 8344 he has a
change from A-G in most of the mitochondrial DNA
from muscle and lymphocytes.The other relatives
have different proportions of the same
mutation,which is in the tRNA for lysine (MT-TK)
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Another mtDNA synthesis mutation3243(AgtG) in the
tRNALeu gene (MT-TL1)
If this mutation is present in 10-30 of the
mtDNA in white blood cells the patient may have
type II diabetes with or without deafness . If
the same mutation is in more than 70 of the
mtDNA the full MELAS syndrome is likely

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Deletions of mitochondrial DNA in muscle biopsies
from individuals with Kearns-Sayre syndrome. DNA
was digested with Pvull, which cuts the
mitochondrial genome at one site, resulting in a
16.5-kb fragments that is detected with a probe
to the mitochondrial DNA by southern analysis.
Each individual with the syndrome has two
populations of mitochondrial DNA one of normal
size and one of smaller size form Zeiani M,
Moraes CT DiMauro S et al. Deletions of
mitochondrial DNA in Kearns-Sayre syndrome.
Neurology 1988 38 1339-1346)
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Three pedigrees of rare families having infants
with fatal mitochondrial disorders showing mtDNA
depletioncaused by mutations in nuclear encoded
mitochondrial genes eg TK2 encoding mitochondrial
Thymidine kinase
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mtDNA contribution to the reconstruction of human
history
Depends on-

• High mutation rate (especially in D loop region)

• Maternal transmission

• No recombination

This allows the origins of female ancestors to be
deduced
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mtDNA phylogenies have suggested a recent African
origin for modern humans
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African origin of modern humans
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Adaptive mutations
Some of the mtDNA variants are found more
frequently in humans in cold climates such as
Siberia and they are thought to alter the balance
of production of energy (ATP) versus Heat per
calorie consumed. It is also suggested that that
the selection of mtDNA variants which allowed
energy production even in time of food shortage
(tight coupling to maximum ATP production) may
now expose us in the presence of excess calories
in food to excess ROS (reactive oxygen species).
This in turn may cause mtDNA damage and
mitochondrial decline that contributes to
metabolic and degenerative diseaes,ageing and
cancer(Wallace 2005)
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References Strachan and Read HMG3 p240-244 Bruce
Korf. Human Genetics A Problem-based approach.
chapter 7 and for the enthusiast http//www.mitoma
p.org/ and Wallace DC. A Mitochondrial Paradigm
of Metabolic and degenerative diseases,Ageign and
cancer A Dawn for Evolutionary Medicine Ann Rev
Genet 200539.359-407