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 .

each of which contains multiple copies of 16. Mitochondrial Genetics • Each cell contains many mitochondria.5-k-b circular DNA molecule • The mitochondrial genome is subject to a number of peculiarities of inheritance .

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

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The nuclear and Mitochondrial genetic codes are similar but not identical .

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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 DNA 46 in diploid cells.The human nuclear and mitochondrial genomes Nuclear Genome Mitochondrial Genome Size 3200 Mb 16. of different DNA 23 (in XX cells) or 24 One circular DNA molecules (in XY cells).6 kb No. of genes ~ 30 000 ~35-000 37 Gene density ~ 1/100 kb 1/0.45 kb . all linear molecule Total no.

. Table continued……. paternal for sequence on Y . 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.

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. All mitochondrial in the zygote are contributed by the egg cell . Sperm mitochondria are shed before entry of the sperm nucleus.

These mitochondria segregate passively when the cell divides. Both wild-type and mutant (gray) mitochondria are included in the hundreds of mitochondria in a cell.Concept of heteroplasmy. This can lead to variation in the proportion of affected mitochondria in different tissues or different individuals in a family .

000 • Sperm few hundred • No mitochondria in red cells and some terminally differentiated skin cells . Number of Mitochondria per cell • Most somatic cells 100-10.000 • Lymphocyte 1000 • Oocytes 100.

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.heart block.Stroke-like episodes LHON (Leber’s Hereditary Optic atrophy) Kearn-Sayre (eye problems.Epilepsy Lactic acidosis.also heart problems) .ataxia ie loss of coordination Leigh syndrome(rare severe brain disease in infancy.

epilepsy.difficulty with vision and hearing.which is in the tRNA for lysine (MT-TK) . Diagnosed as MERRF aged 12 after muscle biopsy.The other relatives have different proportions of the same mutation.lack of progress at school.At postition 8344 he has a change from A-G in most of the mitochondrial DNA from muscle and lymphocytes.Michael presented with muscle problems.

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 .

Moraes CT DiMauro S et al. 38: 1339-1346) . Neurology 1988. DNA was digested with Pvull. Each individual with the syndrome has two populations of mitochondrial DNA: one of normal size and one of smaller size form Zeiani M.Deletions of mitochondrial DNA in muscle biopsies from individuals with Kearns-Sayre syndrome. Deletions of mitochondrial DNA in Kearns- Sayre syndrome. resulting in a 16. which cuts the mitochondrial genome at one site.5-kb fragments that is detected with a probe to the mitochondrial DNA by southern analysis.

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 .

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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 .

mtDNA phylogenies have suggested a recent African origin for modern humans .

…………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).ageing and cancer(Wallace 2005) . This in turn may cause mtDNA damage and mitochondrial decline that contributes to metabolic and degenerative diseaes.

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Ageign and cancer: A Dawn for Evolutionary Medicine Ann Rev Genet 2005.References Strachan and Read HMG3 p240-244 Bruce Korf.mitomap. chapter 7 and for the enthusiast http://www.org/ and Wallace DC.359-407 . A Mitochondrial Paradigm of Metabolic and degenerative diseases. Human Genetics A Problem-based approach.39.