What is metabolism

Metabolism is the sum of all of the enzymes-

catalyzed reactions that take place in cells and
can be viewed as having two contrasting
processes :
* catabolism : energy yielding reactions in which
complex mol are broken down to small molecule
* anabolism : energy requiring reactions in which
simple precursor molecule are converted into complex
mol.
 Energy yielding in catabolism
Catabolism of C-H, lipids, aa to a simpler
end-product such as CO2, H2O and amonia
is accompanied by the synthesis of ATP.
ATP is utilized for various cellular functions
such as :
synthesis of protein,RNA,DNA for growth, adaptation and repair,
synthesis of fat and glycogen,
performance of mechanical work,
active ion transport,
absorptions of nutrients against the gradient.
 Role of Acetyl CoA
lipids polysaccharides proteins

fatty acids monosaccharides amino acids

Acetyl
AcetylCoA
CoA
fatty acids ketone bodies

triglcerides and cholesterol

phospholipids citric acid cycle
bile salts steroids
CO2 + H2O + ATP
 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
 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
 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)
 The nuclear and Mitochondrial
genetic codes are similar but not
identical
The human nuclear and mitochondrial genomes
Nuclear Genome Mitochondrial Genome

Size 3200 Mb 16.6 kb

No. of different DNA 23 (in XX cells) or 24 One circular DNA

molecules (in XY cells); all linear molecule
Total no. of DNA 46 in diploid cells, but Often several
molecules per cell varies according to thousands (but variable
ploidy
Associated protein Several classes of Largely free of protein
histone & nonhistone
protein
No. of genes ~ 30 000 ~35-000 37

Gene density ~ 1/100 kb 1/0.45 kb

 Table continued..
Repetitive DNA Over 50% of genome Very little

Transcription The great bulk of genes are Co-transcription of

transcribed individually multiple genes from both
the heavy and light strands
Introns Found in most genes Absent

% of coding DNA ~ 1.5% ~ 93%

Codon usage Slightly different see slide

Recombination At least once for each pair No evidence for this

of homologs at meiosis occurring naturally

Inheritance Mendelian for sequence on Exclusively maternal

X and autosomes; paternal
for sequence on Y
Oxidative phosphorylation
 The limited autonomy of the mitochondrial
genome
Mitochondrial Encoded by Encoded by nuclear
component Mitochondrial genome genome

Components of 13 subunits 80 subunits

oxidative
phosphorylation
system
Components of 24 approx 80
protein synthesis
apparatus
 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
Mitochondrial inheritance.
Sperm mitochondria are shed
before entry of the sperm
nucleus. All mitochondrial in the
zygote are contributed by the
egg cell
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
 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
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
 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)
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)
Another mtDNA synthesis mutation
3243(A>G) 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
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)
Three pedigrees of rare families having infants with fatal mitochondrial
disorders showing mtDNA depletion;caused by mutations in nuclear
encoded mitochondrial genes eg TK2 encoding mitochondrial Thymidine
kinase
 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

mtDNA phylogenies have suggested a recent
African origin for modern humans
African origin of modern humans
 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)
References
Strachan and Read HMG3 p240-244
Bruce Korf. Human Genetics A Problem-based
approach. chapter 7
and for the enthusiast
http://www.mitomap.org/
and Wallace DC. A Mitochondrial Paradigm of
Metabolic and degenerative diseases,Ageign and
cancer: A Dawn for Evolutionary Medicine
Ann Rev Genet 2005;39.359-407