1) Mitochondria are cellular structures that produce energy and were discovered in the late 1800s. They have a double membrane structure and contain their own DNA. 2) Mitochondrial DNA is much smaller than nuclear DNA and is only passed down from mothers. It can mutate at a higher rate and mutations can cause over 100 human diseases. 3) Common mitochondrial diseases include LHON (optic nerve disease), MERRF (myoclonic epilepsy), CPEO (eye muscle weakness), and MELAS (stroke-like episodes). These diseases demonstrate mitochondrial inheritance patterns and can be caused by DNA deletions or point mutations.

1. MITOCHONDRIAL DNA
Mitochondrial Disease
Supervisor by: Nouf Al-Sultan.
Preparation: Ala’a Al-Ruwaisan.
inter membrane space
kingdom Saudi Arabia
King Saud University
College of Science
Department of Zoology
Cytology, genetic and histology

2. Objectives:
1. Who Discovered the Mitochondria?
2. What are Mitochondria?
3. Structure of Mitochondria.
4. What is mitochondrial DNA?
5. Characteristics of mitochondria dna.
6. NUCLEAR DNA VS MITOCHONDRIAL DNA.
7. Schematic representation of mammalian mtDNA.
8. The RITOLS model of mitochondrial DNA replication.
9. What is Mitochondrial Disease
1.Replicative Segregation
2.Homoplasmy and Heteroplasmy
3.Maternal Inheritance
1o- Why is mitochondrial mutation so high?
11- Type Disease of Mitochondria
12- New gene therapy for mitochondrial diseases a
step closer thanks to ONPRC
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3. Discovered the Mitochondria:
• There isn't one single person credited with discovering
the mitochondria, as over the years a number of
scientists have made important contributions to the
study of the discovery of this important cellular
structure:
• 1800s In 1857, Albert von Kölliker described what he
called “granules” in the cells of muscles.
- Other scientists of the era also noticed these
“granules” in other cell types.
• 1886 , when Richard Altman, a cytologist, identified
the organelles using a dye technique, and dubbed them
“bioblasts.” He postulated that the structures were the
basic units of cellular activity.
• 1898, Carl Benda coined the term mitochondria. He
derived the term from the Greek language for the words
thread, mitos, and granule, chondros.
-Though mitochondria are an integral part of the
cell, evidence shows that they evolved from primitive bacteria.
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4. What are Mitochondria?
• Mitochondria are specialized structures unique to
the cells of animals, plants and fungi.
• They serve as batteries, powering various
functions of the cell and the organism as a
whole..
• In nearly every cell in the body, Mitochondria are
responsible for producing energy (called ATP)
that the cell needs to function.
• They are like power stations in our bodies,
supplying the energy every cell needs to function.
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5. Mitochondria Structure:
• Mitochondria are rod shaped structure found in both
animal and plant cells.
• It is a double membrane bound organelle. It has the
outer membrane and the inner membrane. The
membranes are made up of phospholipids and
proteins.

6. Mitochondria Structure:
• The components of mitochondria are as follows:
• Outer membrane:
It is smooth and is composed of equal amounts of
phospholipids and proteins.
• It has a large number of special proteins known
as the porins.
• The porins are integral membrane proteins and
they allow the movement of molecules that are
of 5000 daltons or less in weight to pass
through it.
• The outer membrane is freely permeable to
nutrient molecules , ions, energy molecules
like the ATP and ADP molecules.

7. • Inner membrane:
The inner membrane of mitochondria is more complex
in structure.
• It is folded into a number of folds many times and is
known as the cristae.
• This folding help to increase the surface ares inside
the organelle.
• The cristae and the proteins of the inner membrane
aids in the production of ATP molecules.
• Various chemical reactions takes place in the inner
membrane of the mitochondria.
• Unlike the outer membrane, the inner membrane is
strictly permeable, it is permeable only to oxygen,
ATP and it also helps in regulating transfer of
metabolites across the membrane.
Mitochondria Structure:

8. • Intermembrane space:
It is the space between the outer and inner
membrane of the mitochondria, it has the same
composition as that of the cell's cytoplasm.
• There is a difference in the protein content in
the intermembrane space.
• Matrix:
The matrix of the mitochondria is a complex
mixture of proteins and enzymes. These
enzymes are important for the synthesis of
ATP molecules, mitochondrial ribosomes, tRNAs
and mitochondrial DNA.
Mitochondria Structure:

9. What is mitochondrial DNA
• Mitochondrial DNA or mtDNA or mDNA is
the DNA in the mitochondria, rest of the
DNA present in the eukaryotic cells is in the
nucleus, in plants DNA is also found in
chloroplasts.
• The mitochondria have a small amount of
DNA of their own.
• Human mitochondrial DNA spans about
16,500 DNA base pairs, it represents a small
fraction of the total DNA in cells. The
mtDNA contains 37 genes. All these genes
are essential for normal function of the
mitochondria.
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10. Characteristics of mitochondria DNA:
• Is inherited exclusively from the mother!
mtDNA is a circular shape single
chromosome
• It is only 16 kb in length - contains 16,600 bp.
• Codes for 37 genes.
• Contains 22 tRNA and 2 rRNA coding genes.
• Encodes 13 proteins that are subunits of oxidative
phosphorilation.
• Contains only exons, no introns.
• Has no reparation system – high mutation rate
especially in D-loop!
• No crossing over.
• Replicative segregation, homoplasmy &
heteroplasmy
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11. • Nuclear DNA
– found in nucleus of
the cell
– 2 sets of 23
chromosomes
– maternal and
paternal
– can "discriminate
between individuals
of the same
maternal lineage“
– double helix
– bounded by a
nuclear envelope
– DNA packed into
chromatin
• Mitochondrial DNA
– found in mitochondria of
the cell
– each mitochondria may
have several copies of
the single mtDNA
molecule
– maternal only
– cannot "discriminate
between individuals of
the same maternal
lineage“
– Circular
– free of a nuclear
envelope
– DNA is not packed into
chromatin
Nuclear DNA vs. Mitochondrial DNA

12. Schematic representation of mammalian mtDNA.
Chan Bae Park, and Nils-Göran Larsson J Cell Biol 2011;193:809-818
© 2011 Park and Larsson
1. the double-stranded circular mammalian mtDNA
2. molecule of ∼16.5 kb contains
3. Asingle longer noncoding region, the displacement loop (D loop) region.
4. harboring the promoters for transcription of both mtDNA strands (HSP and
LSP) and the origin of leading strand replication (OH).
5. The origin of lagging strand replication (OL) is embedded in a cluster of
tRNA genes.
6. The genes for the two rRNAs (12S and 16S rRNA),.
7. 13 mRNAs (ND1–6, ND4L, Cyt b, COI–III, ATP6, and ATP8),.
8. 22 tRNAs (F, V, L1, I, M, W, D, K, G, R, H, S1, L2, T, P, E, S2, Y, C, N, A,
and Q) are indicated by boxes. Illustration by Annika Röhl.

13. The RITOLS model of mitochondrial DNA replication.
Ian J. Holt, and Aurelio Reyes Cold Spring Harb Perspect Biol 2012;4:a012971
©2012 by Cold Spring Harbor Laboratory Press
The RITOLS model of mitochondrial DNA replication. Replication initiates at
one of two sites (OH or Ori-b), here conflated to OR, for origin of replication.
Leading strand DNA synthesis progresses with concurrent incorporation of RNA
on the lagging strand. At some point (frequently OL), lagging strand DNA
synthesis initiates and the lagging strand RNA is replaced by, or converted to,
DNA.

15. Disease of Mitochondria
• More than 100 different rearrangements and
100 different point mutations have been
identified in mtDNA that can cause human
disease, often involving the CNS and
musculoskeletal system
• The diseases that result from these mutations
show distinctive pattern of inheritance because
of 3 unusual features of mitochondria.
1.Replicative Segregation
2.Homoplasmy and Heteroplasmy
3.Maternal Inheritance

16. 1.Replicative Segregation
• At cell division, multiple copies of mtDNA
in each of the mitochondria in a cell
replicate and sort randomly among newly
synthesized mitochondria.
• The mitochondria in turn are distributed
randomly between the 2 daughter cells.
This is called as replicative segregation.
• The first unique feature of mitochondria
is the absence of tightly controlled
segregation seen during mitosis and
meiosis of the 46 nuclear chromosomes.
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17. 1.Replicative Segregation

18. 2.Homoplasmy and Heteroplasmy
• One daughter cell may by chance receive
mitochondria that contain only a pure
population of normal mtDNA or a pure
population of mutant mtDNA
(Homoplasmy)
• The daughter cell may receive a mixture of
mitochondria some with and some without
mutation (Heteroplasmy)

19. 2.Homoplasmy and Heteroplasmy

20. 3.Maternal Inheritance of mtDNA
• Sperm mitochondria are generally
eliminated from the embryo so that
mtDNA is inherited from the mother.
• All children of a female who is
homoplasmic for a mtDNA mutation will
inherit the mutation
• None of the offspring of a male carrying
the same mutation will inherit the
defective DNA
• Maternal inheritance of a homoplasmic
mtDNA mutation causing Leber
Hereditary optic neuropathy is known.
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22. Why is mitochondrial mutation so high?
• The mitochondrial genome has a very high
mutation rate, 10- to 17-fold higher than
that observed in nuclear DNA.
• Although mtDNA repair systems do
exist and , they are not sufficient to
counteract the oxidative damage sustained by
the mitochondrial genome.
• Protective histones are also lacking.
• Oxygenation process is high percentage.
• The mtDNA mutation rate can be increased
by environmental agents or by mutation of
nuclear genes involved in mtDNA maintenance
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23. • It has been identified in mtDNA:
(1) missense mutations in the coding
regions of genes that alter the activity
of an oxidative phosphorylation protein;
(2) point mutations in tRNA or rRNA
genes that impair mitochondrial protein
synthesis;
(3) Deletions or duplications of the
mtDNA molecule. They are generally
somatic in origin, although a small
proportion is inherited, in some
diseases.
THREE TYPES OF MUTATIONS
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24. Type Disease of Mitochondria
1. Alpers Disease
2. Barth Syndrome / LIC
(Lethal Infantile
Cardiomyopathy)
3. Beta-oxidation Defects
4. Carnitine-Acyl-Carnitine
Deficiency
5. Carnitine Deficiency
6. Creatine Deficiency
Syndromes
7. Co-Enzyme Q10
Deficiency
8. Complex I Deficiency
9. Complex II Deficiency
10.Complex III Deficiency
11. Complex IV Deficiency /
COX Deficiency
12.Complex V Deficiency
13.CPEO
14.CPT I Deficiency
15.CPT II Deficiency
16.KSS
17.Lactic Acidosis
18.LBSL - Leukodystrohpy
19.LCAD
20.LCHAD inter membrane space

25. Type Disease of Mitochondria
21.Leigh Disease or Syndrome
22.Luft Disease
23.MAD / Glutaric Aciduria Type II
24.MCAD
25.MELAS
26.MERRF
27.MIRAS
28.Mitochondrial Cytopathy
29.Mitochondrial DNA Depletion
30.Mitochondrial Encephalopathy
31.Mitochondrial Myopathy
32.MNGIE
33.NARP
34.Pearson Syndrome
35.Pyruvate Carboxylase Deficiency
36.Pyruvate Dehydrogenase Deficiency
37.POLG Mutations
38.Respiratory Chain
39.SCAD
40.SCHAD
41.VLCAD
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27. 1.LHON
• Disease Description:
• Leber’s Hereditary Optic Neuropathy, also
called LHON or Leber’s (LAY-bers), is a rare
condition which can cause sudden, profound,
painless loss of central vision.
• While symptoms can begin at any age and in
men or women, it is most common among men
around age 20.
• LHON is an extremely rare genetic disorder
that is passed through the egg cell of the
mother.
• These mutations can lead to the reduction in
cellular energy production, which in turn results
in cell damage and death of certain optic nerve
cells.
• average 50% of men and 15% of women with
a LHON mutation will lose vision in their
lifetime.

28. 2.MERRF (Myoclonic Epilepsy with Ragged
Red Fibres)
• Long Name: Myoclonic Epilepsy and Ragged-Red
Fiber Disease.
• Symptoms: Myoclonus, epilepsy, progressive
ataxia, muscle weakness and degeneration,
deafness, and dementia.
• Cause: Mitochondrial DNA point mutations:
A8344G, T8356C
• MERRF is a progressive multi-system syndrome
usually beginning in childhood, but onset may
occur in adulthood.
• The rate of progression varies widely.
• Onset and extent of symptoms can differ
among affected siblings.
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30. 3.CPEO
• Long Name: Chronic Progressive External
Ophthalmoplegia Syndrome.
• Symptoms: visual myopathy, retinitis
pigmentosa, dysfunction of the central
nervous system.
• Cause: Single mitochondrial DNA deletions.
Mitochondrial DNA point mutations:
A3243G (most common)
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32. 4. MELAS
• Long Name: Mitochondrial Encephalomyopathy
Lactic Acidosis and Strokelike Episodes.
• Cause: Mitochondrial DNA point mutations:
A3243G (most common)
• MELAS is a progressive neurodegenerative
disorder with typical onset between the ages
of 2 and 15, although it may occur in infancy
or as late as adulthood. Initial symptoms may
include stroke-like episodes, seizures, migraine
headaches, and recurrent vomiting.
• Typically, the age of death is between 10 to
35 years, although some patients may live
longer.
• Death may come as a result of general body
wasting due to progressive dementia and muscle
weakness, or complications from other affected
organs such as heart or kidneys.
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33. • Mitochondrial DNA schematically depicted as circular double-strand
DNA with some mutation syndromes.
• MIDDM = maternally inherited deafness and diabetes mellitus;
MELAS = mitochondrial encephalomyopathy, lactic azidosis and
stroke-like episodes; DIDMOAD = diabetes insipidus, diabetes
mellitus, optic atrophy, and deafness; KSS = Kearns-Sayre syndrome;
LHON = Leber‘s hereditary optic neuropathy; MERRF = myoclonic
epilepsy, ragged-red fibers; NARP = neuropathy, ataxia, and retinitis
pigmentosa.

34. Figure 2 The mitochondrial morbidity map
DiMauro, S. et al. (2013) The clinical maze of mitochondrial neurology
Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.126

35. Other disorders
• A buildup of somatic mutations in
mitochondrial DNA has been associated
with an increased risk of certain age-
related disorders such as heart disease,
Alzheimer disease, and Parkinson disease.
Additionally, research suggests that the
progressive accumulation of these
mutations over a person's lifetime may
play a role in the normal aging process.
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36. New gene therapy for mitochondrial
diseases a step closer thanks to ONPRC

37. Any question

38. References
• Human Mitochondrial DNA Replication , Ian J.
Holt and Aurelio Reyes
• The mitochondrial genome: structure, transcription,
translation and replication, Taanman JW1, 1999 Feb.
http://www.sciencedirect.com/science/article/pii/S00
05272898001613
• Mitochondrial DNA mutations in disease and aging Chan
Bae Park1 and Nils-Göran Larsson2
• Mitochondrial DNA mutations in human disease Robert
W. Taylor & Doug M. Turnbull
• http://www.childneurologyfoundation.org/disorders/mi
tochondrial-diseases/
• http://www.smw.ch/content/smw-2012-13690/
• Novel techniques for the prevention of mitochondrial
DNA disorders an ethical review

39. Good luck