1. Mitochondria are unique intracellular organelles They contain their own DNA which forms the proteins involved in oxidative phosphorylation ( the chemical process which creates energy ) Unlike nuclear DNA, mtDNA does not bind to a histone protein. It is replicated by DNA Polymerase Gamma Each mito. has two or three copies of its mtDNA, therefore there are several thousand copies in each cell.

2. The human mito. genome is very small It encodes the genes involved in energy production: -seven proteins of complex I of the respiratory chain -transfer DNA’s, two subunits of ATP synthase, and a few other subunits to complexes III, IV, and V It is now widely accepted that mtDNA is continuously exposed to heavy free radical activity Free radicals cause damage to mito. Membranes and to the mtDNA itself. Some of these radicals include: -semiquinone radicals -superoxide and hydroxyl radicals

3. The rate of mutation in mtDNA is much higher than in nuclear DNA, and the rate of mtDNA mutations increase with age Mitochondria’s proximity to the free radicals that they produce, along with their intricate structure, makes them particularly vulnerable to oxidative damage Plus, mtDNA is not as well protected as nuclear DNA, which is coated by proteins. Therefore, mtDNA is an easy target The accumulations of mito. genome damage during a life time causes a decline in many biological events involved in the production of energy. This then depletes the vitality of the organism or, in some cases, can lead to disease.

4. Optic Nerve Disease- LHON Picture courtesy of http://kaifuwu.com/lhon/NeurochemInt.pdf

5. Leber's Hereditary Optic Neuropathy (LHON), also known as Leber's Optic Atrophy (LOA), Leber's Optic Neuropathy (LON) or Leber's Disease. It is often referred to as just Leber's for short. History: The disease was first described by the German eye specialist Theodore Leber in 1871.

6. Leber's Hereditary Optic Neuropathy is a rare condition which can cause loss of central vision. LHON is a form of midlife onset, acute or subacute blindness, leading to central scotoma. It usually affects men; it is known as a missense mutation of the mtDNA.

7. mtDNA and LHON 19 mutations have been reported to be associated with LHON, 5 appear to play a primary role in causing the disease a G-to-A transition at np 14459 in the ND6 gene (MTND6*LDYT14459A). a G-to –A transition at np 11778 in the ND4 gene (MTND4*LHON11778A)

8. a G-to-A transition at np 3460 in the ND1 gene (MTND1*LHON3460) a T-to-C transition at np 14484 in the ND6 gene (MTND6*LHON14484C) G-to-A transition at np15257 in the cytb gene (MTCYB*LHON15257A) All five of these mutations can result in the same phenotype (blindness), they differ in their severity

9. MTND6*LDYT14459A mutation is by far the most severe of the LHON mutations. It can significantly reduce reproductive fitness. MTND4*LHON11778A mutation is the most common cause of LHON, accounting for 50% of European cases and > 90% of Asian cases. MTND6*LHON14484C is a significantly milder mutation, it accounts for about 15% of cases, associated with 37% spontaneous visual recovery. Frequently found in association with other LHON mutations.

10. Chemicals embedded in the mitochondrial membrane Cause of LHON **There are several genetic defects which can cause LHON. They all change the structure of these chemicals embedded in the mitochondrial membrane. Changing the structure of the chemical makes it less good at its job, so the body gets less energy. Mitochondria membrane magnified

11. Deafness as a Mitochondrial Disorder Hearing Impairment is Common in Various phenotypes of the Mitochondrial DNA A3243G mutation 3243 is the most common mtDNA mutation that occurs in hearing loss

12. Sensorineural Hearing Loss Damage to the structures of inner ear can cause: Progressive Sudden But ALWAYS permanent

13. How Does Mutation Effects The Ear The concentration of endolymph, the fluid covering the hair cells, are maintained at a high positive resting potential. This is essential for normal hair cell function. When a mutation occurs in the inner ear the endolymph reduces to zero. Resulting in deafness.

14. Prevention/Treatment No hearing loss “Cure” Many Researchers are continuing to work on this area. Promising Developments are: Hearing Aids Assistive Listening Devices Cochlear Implants Hair Cell Regeneration It is the growing of new cochlear cells to replace damaged or missing hair cells that cause hearing loss.

15. The diagram shows the parts of a cochlear implant in place in a user's ear. Parts a, b, c and d are external parts; parts e and f are internal. A. microphone (worn behind the user's ear); B. thin cord (connects microphone to speech processor); C. speech processor (codes sounds electronically); D. transmitting coil (sends code as radio waves); E. receiver/stimulator (converts code into electrical signals); F. electrode array implanted in the cochlea (stimulates auditory nerve fibers when electrical signal is received); G. cochlea; H. auditory nerve.

16. Mitochondrial Dna’s effect on the heart Hard to believe that muscle as large and important as the heart can be stopped by something so small as a deletion in the DNA of mitochondria.

17. -Mitochondria in the heart are affected by the oxidative free radicals just as they are elsewhere in the body. -The oxidative free radicals specifically seem to target a particularly large section of 4977 base pairs of the mitochondrial DNA between 8470 and 13446. -Cardiac tissue depends heavily on mitochondria for oxidative energy generation, and such energy is indispensable for atrial contraction and for maintenance of normal atrial cellular function. It has been reported that somatic mitochondrial DNA (mtDNA) mutations might be a result of wear and tear and their accumulation may contribute to aging and progressive organ dysfunction.

18. In this graphic base pairs 8470 thru 13446 begin approximately at the bottom (1) and end about (2). This large deletion causes a lot of proteins to no longer be translated. Which in turn causes less energy to be made in the mitochondria. <--- 2  1

19. This graphic shows one possible link to the reason that the older a person is the higher the likelihood of them having AF. This could also be a reason why the older a person is the more likely they are to have a heart attack. This graph shows the correlation between age, deletion and AF (atrial fibrillation). This shows that the people who do have atrial fibrillation have a much higher incidence of mitochondrial deletion in this area.

20. How do the deletions in mitochondrial DNA effect the heart? 1) The mitochondria produce less energy for the heart resulting in decreased cardiac output, heart failure, and systemic embolization, and is associated with significant morbidity and mortality. 2) The mitochondria get more oxidative free radicals when the heart starts failing making the mitochondrial situation worse. 3) The deletion does not happen in all of the mitochondria at once, so there are still mitochondrion in the patients that are functioning normally. This is also why the levels of the deletion went up with age even in the patients that had the AF.

21. By using the large number of bp variants of the non-coding control region, researchers can identify someone from a very small amount of mtDNA With this specific knowledge, mtDNA typing can provide info. about the relationship of an individual to a sample. Therefore, mtDNA mutations can be traced around the globe

22. Mervi Lehtonen Department of Neurology, University of Oulu Department of Medical Biochemistry and Molecular Biology, University of Oulu Biocenter Oulu, University of Oulu http://herkules.oulu.fi/isbn9514268490/html/index.html Mitochondrial DNA Damage and Dysfunction Associated With Oxidative Stress in Failing Hearts After Myocardial Infarction Tomomi Ide 1, Hiroyuki Tsutsui 1, Shunji Hayashidani, Dongchon Kang, Nobuhiro Suematsu, Kei-ichiro Nakamura, Hideo Utsumi, Naotaka Hamasaki, Akira Takeshita http://circres.ahajournals.org/cgi/content/full/88/5/529 Mitomap.org Pictures