1. Mitochondrial Dysfunctional Activity and the relationship with Parkinson’s disease<br />Carlos Santos-Pérez<br />Department of Biology, University of Puerto Rico, Cayey Puerto Rico<br />______________________________________________________________________________<br />Abstract<br />Parkinson Disease is one of the most dangerous neurodegenerative diseases. The symptoms of this disease can be stiffness of the muscle, trembling and also difficulty in swallowing, speaking and chewing. Some studies and researches found a relationship between Parkinson Disease and Mitochondrial Dysfunctional Activity. In fact the researchers discuss that the p53 agent could be a pro apoptotic agent and in that way it could help to the death of the dopaminergic cells. This dopaminergic cells are the cells that controls the movement specifically the motor system. Also it exists some proapoptotic agents and agents that inhibit the apoptotic phases. It have been proven that the mitochondrial activity of the cell regulate this apoptotical function. It can be inferred from that position that it can exists a relation between the DNA that contain the mithocondria and its activity. That’s why it can be mention that polymorphism can be mediators in the deregulation of the complex I activity of the electron transfer chain reaction of the cellular respiration. On the other hand researchers mentioned in this review paper found that polymorphism are not the causes of the Dysregulated Activity of the Mithocondria. This decreasing activity of the Complex I of the Electron Transfer Chain is because of the presence of neurotoxin that is also proapoptotic factors. In addition it has to be mention that this decreasing of the mitochondrial activity it is not only because of the neurotoxin it is also because of the presence of Calcium in the cells. <br />______________________________________________________________________________<br />Introduction<br />Parkinson Disease is the second most common neurodegenerative disorder after the Alzheimer Disease. The sings and symptoms of this disease can be stiffness of the muscle, trembling and also difficulty in swallowing, speaking and chewing. It’s known that it is cause by the absence of dopaminergic neurons in the substancia nigra pars compacta and other nerves that are related with the stratium. For that reason the brain doesn’t have the enough neurotransmitter, that it’s called dopamine, to maintain a regulation of the Motor System. This disease can affect at least 4 million people in the United States of America each year. On the other hand the origin of the Parkinson Disease and the death of the dopaminergic neurons are unknown. Some of the fact that can represent a presage to find why this disease is affecting so many people is the relationship with Mitochondrial Dysfunction. In addition there is a possible relation between Mitochondrial Dysfunctional Activity and Programmed Cell Death or Apoptosis. <br />Mithocondrial Activity is characterized by the metabolism activity that implicate energy production in the cell but it have to be known that mitochondria contain its own DNA. This DNA can encode 13 proteins that are involved in phosphorylation reactions and 22 tRNA that are involve in the process of Cellular Respiration (Shults 2004). The Mitochondrial Activity doesn’t represent only a process that is reserved for the mitochondria because it’s also know that dysfunctional activity of the mitochondria can affect the Calcium and Potassium Channels (that are related with the synaptic activity between the neurons) and debacle the process that are related with the calcium production in the Endoplasmic Reticulum. It is also known that imbalance in the Redox reaction can propitiate the apoptotic activity in Dopaminergic Neurons. <br />Mitochondrial Apoptosis Activity and p53<br />Apoptosis is defined by the regulation of the death activity of the cells. This process allows the cells to disappear without expulsing harmful substances that can affect other cells. It is also important to know that apoptotic activity affect normally unnecessary cells, old cells and unhealthy cells (cells that are invaded by a virus). The mitochondria have a principal role in the apoptotic activity of the cells. Accumulated evidence has shown that an irregular apoptotic activity can represent an excess death activity of dopaminergic neurons (Andersen 2001). There are two possible pathways that can be a signal for apoptotic activity: external and internal (Reed 2002). There are some proapoptotic factors that are involve in both of the pathways. For example when a cell suffer of tumorgenesis or the cell cycle is abnormal the mitochondria release the proapoptotic factor name cytochrome c, consequently this activate the caspases pathways and the inhibition of the protein caspases. (Shapira and Orth 2001) There are other apoptotic factors such as a flavoprotein named Apoptotic-inducin factor 1 that is involve with the nuclease and nuclease activators. This flavoprotein synthesis is supposed to be genetically controlled. Also another proapoptotic factors are the members of the Bcl-2 family of protein (Shultz 2004). This protein family has a close relationship to a tumor suppressant named p53. This p53 protein can mutate and can mediate in a deregulation of the Bcl-2 family of protein in the mitochondria. This can cause an apoptosis that it’s not necessary at the moment. That’s what happens in some of the Parkinson’s disease patients. To prove this relation between the apoptosis, mitochondrial activity and the expression of the p53 protein there are some researches that are based in post-mortem, in vitro and in vivo subjects. In the pos-mortem tissues with Parkinson Disease that was evaluated by Monte et al in 1998 there was an increase of p53 expression of the patient dopaminergic cells. Also the expression of phospho 38 increase causing a deregulation in the MAPK pathway (responsible of phosphorilation) and for that reason a excessive production of mutated p53. <br />In the case of in vitro and in vivo models of Parkinson Disease, the researchers uses 1-methyl-4phenyl-1,2,3,6-tetrachydropyridine (MPTP), Rotenone and also 6-hydroxydopamine that are mediators to abrogate for dysfunctional activity in the Complex I of the mitochondria to cause and induce Parkinson Disease to animal and for in vitro cases.(Blum et al 2001) This model represent a very strong relation between the expression of a mutated p53 form and the toxins that abrogate for the dopaminergic cell damage. So basically it can be establish that it’s like a linear reaction. There is damage because the Parkinson Disease profactors in the Complex I of the mitochondria, this cause an increase in the p53 mutate form and this can lead to unnecessary apopototic activity in the dopaminergic neuron of the nigral substancia. (Blum et al 2001) <br />Decreasing of the Complex I Activity and Cellular Respiration<br />There is a very close relation between the reduction of the complex I of the mitochondria and the neurotoxin that presage the irregular synaptic process between the dopaminergic cells. Winkfholer and Haas in 2009 confirmed what Schapira et al 1990 established. They studied selected regions in the brain and also researched tissues that were from Advanced Pakinson Disease Patients. His studies are relevant because they found a significant reduction in activity of the complex I in the mitochondria. These researchers also reason about that the medication of the Parkinson Disease Patients can be provoking the deregulated behavior of the mitochondria. That’s why Haas and Shults in 2004 design a methodology that involves some variables that Schapira’s research didn’t evaluate. They evaluate and compared untreated and early PD, age and gender matches control. The results of this research was that early and untreated patients have a Dysfunctional Mithocondrial activity specially in the Comples I and III.(Shults 2004).<br />On the other hand the cause of this is related with MPTP. This neurotoxin is metabolized by mitochondrial monoamine oxidase (Chiba et al 1984; Barnajee et al 2008) This neurotoxin accumulates in the mitochondrial and quickly affect the electron transport chain of the Cellular Respiration. Also this is also due to the evidence that implicate the free radical induced oxidative stress.<br />Association of Mitochondrial Polymorphism <br />There is a reduction of the Complex I mitochondrial activity and an effect of this situation is that the neurotoxin MPTP accumulate in the mitochondria and create the Parkinsonism and also result in an increase NO production. Previosly studies have shown that Nitric Oxide in a pathological function can provoke DNA damage, lipid peroxidation, proteins nitrsylation and mythocondrial dysfunction (Huerta et al. 2006). These are some factors that are correlated with PD. For that reason Iadecola, Zhang et al. researched about the presence of an isoform of NO call iNOS in the glial cells of the brain. These researchers found that in autopsied PD patients the levels of iNOS and nNOS are increased in comparison with healthy patients. <br />This excessive amount of iNOS and nNOS are related with the production of NOS in the subsantia nigra. It can be inferred form this that Nitric Oxide overproduction in the cells sepecially in the neuronal cells may cause the formation of free radicals that can contribute with the death of neuronal cell and every type of cells. This can explain the existence of PD because NO can be the apoptotic agent of the dopaminergic cells. The problem is that the production of the NO and NOS is correlated with the genetic of the mitochondria. It can be from a very direct mutation from recessive and dominant forms of PD but also it can be from common DNA variants like polymorphism. <br />There is when a researcher can incorporate the theory that the histones and the introns and extron can affect the patient that have Parkinson Disease but also can affect to provoke the formation of PD. <br />To prove this theory the researchers Huerta et al. prepare a methodology that involve to genotyped at least 450 PD and control patients for two mitochondrial polymorphisms that have been previously link to PD. They follow a saltin method to genomic the DNA form the patients of PD and also the control group. For the iNOS and the nNOs polymorphism, the product of the PCR wre digested in the restriction enzyme NcoI and processed through electrophoresis in a 3% agarose gells. Also the eNOS polymorphism was PCR processed with ethidium-bromide slating and pass through electrophoresis in a 4% agarose gels. The result was that Genotype frequencies according to the Hardy Winberg equilibrium for the three polymorphism wer optimus and there was not a significant increase in the presence of the three polymorphism in the genetic of mtRNA in the mitochondria. The frequencies were similar between the control group and the PD patients group. Also allele and genotype did not differ in the mitochondria of both group. (Huerta et al. 2006)<br />In conclusion there is not a significant association between the polymorphism that induce the Dysfunctional activity of the Complex One in the Electron Carrier Channel process in the mitochondria and the Parkinson Disease. Also we can conclude that any polymorphism of NO is related with the apoptotical activity of the dopaminergic cells that are in the substancia nigra pars compacta and in other parts of the body like the Gastrointestinal tract that have a very increase production in comparison with other system of the body of Nitric Oxide. <br />Endoplasmic Reticulum and Mitochondrial Dysfunctional Activity<br />Parkinson Disease, a progressive neurodegenerative disease, can be related with the Endoplasmic Reticulum Stress and dysfunction of the mitochondria in the dopaminergic neurotransmission cells. The researches establish this hypothesis: the calcium is the mediator between the Endoplasmic Reticulum and the Mitochondria crosstalk causing a series of signal that is traduce by the cell in apoptosis (Cell Death). To prove this they use two principal methods: the first is to indentify how much NADH is synthesizes by the mitochondria during the Cellular Respiration and the second is a fluorometric measurement of ER and Mitochondria Calcium levels. The results of this research were that the hypothesis was true. They found that when MPP+ (neurotoxin) increase, the activity or the mitochondria decrease causing the apoptosis. Also they discovered a wide relation between the calcium and the mitochondria apoptotic activity. (Moniz et al 2009)<br /> <br />Deletion of mitochondrial DNA agents that can induce PD<br />Mitochondrial 4977b deletion had proven to be related with the Parkinson Disease and the movement disorders cause by the neurological system but there is a conflict between what caused the deletion of this mtDNA: the aging or the PD itself. The researches are trying to prove that the deletion of this mtDNA is caused by the nigral neurons of the patients that have PD. The process or methodology that they were using was the use of insidious hybridization assay. The have a population of 47 PD patients. Finally they found that the PD was not related with the Mitochondrial 4977b deletion. Furthermore, the aging in conjunction with the PD was not the cause of the Deletion. They conclude that maybe the deletion it’s not directly related with the PD. On the other hand they expressed that if this is right then it have to be that the mutations are affecting the complexes of the mitochondria and this is affecting the apoptotic activity of this neurotransmission cells. (Zhang et al 2002). <br />The imbalance of Redox in Patient with Parkinson Disease and Oxidative Stress<br />The autooxidation of the dompamine drive to the production of semiquinones that are very reactive compounds of the cellular respiration that occurs specifically in the Electro Trasnfer Chain that can also generate free radicals. These free radicals can induce the apoptosis of the dopaminergic cells. But something that it is more important is that the enzymatic pathway of the dopamine doesn’t only conduct to produce determined metabolites they also tend to produce acids that are very dangerous for the DNA and also for the apoptosis of the cell. They are like cell oxidative that if the mitochondria don’t regulate the functions of this compound then will be very negative for the substancia nigra. <br />In addition to that we add the effect of the Levodopa and this can create an overproduction of hydrogen pyroxide that is also negative for the dopaminergic cells because accelerate the process of apoptosis. This is very present in the initial times of the Parkinson Disease Patients. On the other hand in normal conditions the Hydrogen Pyroxide should be inhibit by glutation in a catalyze reaction of the glutation proxidase enxyme. But if this system doesn’t function well then this Peroxide of Hydrogen will be an OH-. <br />Also in this type of patient some research found that there is and over presence of Iron in the nigra susbstancia. This Iron cans reaction like the peroxide of hydrogen in the first case because it is also a free radical that produces the mitochondria that it’s not good for the apoptosis activity. In addition this kind of oxidative stress can affect6 the mitochondrial DNA and this can create little polymorphism that are not related with the NO polymorphism but there is not enough information to said and establish what type of Polymorphism are. In physiological situation or in health patient situation there will be equilibrium between the free radicals and the other compounds but in the case of Parkinson Disease patient this balance or this equilibrium it is not well. That is when the researcher has to think in the imbalance of Redox activity. (Andersen and Chinta 2008)<br />Conclusion<br />In conclusion it can be infer that neurotoxins are not the only the factors that may affect the dopaminergic cells. This review paper has the enough information to confirm that there are more factors that can influence in the death of the dopaminergic cell. It have been mention that polymorphism specifically of NOS can be one of the factors that affect the life of the domapinergic cells but the researcher evaluate that this was not true. Also it have been evaluate about the p53 agent and the proapototic factors that are stimulated by some Parkinson Disease factors that it can be found in the cell. It can be established that this cause it’s more attractive to be the presage of the Parkinson Disease. In addition it can be mention tha the complex I and the NADH are the responsible of the apoptosis in the dopaminergic cells. In the case of the decreasing of the Complex I of the Electron Trasnfer Chain Reaction of Also we have the conclusion that can be establish that it’s like a linear reaction. There is damage because the Parkinson Disease profactors in the Complex I of the mitochondria, this cause and increase in the p53 mutate form and this can lead to unnecessary apopototic activity in the dopaminergic neuron of the nigral substancia.<br />Also it have to be mention that the oxidative stress is one of the mos common causes of the Parkinson Disease because this can cause a deregulated activity in the Cellullar Respiration and in that way in can also affect the apoptosis of the Dopaminergic Cells. This is related also with the free radicals that are neurotoxic. It can be infer that mitochondria it’s not only the center of metabolism because it is also the center of so many other things that can be positive or negative for the body. <br />References<br />Moniz D, Esteves R, Cardoso S, Oliviera C. 2009. Endoplasmic Reticulum and Mitochondria interplay mediates apoptotic cell death: Relevance To Parkinson’s Disease. 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