Structural Biochemistry/Mitochondrial Diseases

Mitochondrial Dysfunction

Mitochondrial dysfunctions are developed from mutations in the mitochondrial genome or DNA during replication. The mutation may be genetic or simply a random mutation in the genome of the individual itself. The patient does not need to obtain the genetic mutation from both parents; one parent is enough to cause this harmful disease. These mutations lead to a less effective mitochondria. They also usually are caused through stress related effects by the reactive oxygen species (ROS). A less effective mitochondria in this case is when the mitochondria is not able to make enough energy to support the whole body. This in turn will lead to many diseases caused from all different organelles from the body. In severe cases, not only will diseases develop but death may even occur.

Mitochondrion is the organelle in organisms that makes energy for most of the reactions in a cell. Mitochondria are found in plant and animal cells; they exist in almost all cells because they are needed to change energy from one form to another. Mitochondria make most of the energy needed in the human body; thus, without their proper function, they will not be able to carry out many of the reactions of the cell throughout the body. They have many physiological functions; for example, they change the food that is consumed by people into ATP, which is a form of energy that the cells are able to use to carry out reactions that the cells need to accomplish.

Overview

Studies and research has shown that Mitochondrial dysfunction is linked to both aging processes and many other diseases. Scientists claim that in order to maintain the function of the mitochondria, then proteins must be observed and watched at all times by chaperones and proteases.

Chaperones are proteins that assist other proteins in forming a polypeptide bond. Thus, in this case, they are proteins that assist the mitochondrial proteins and by watching them. Whereas, proteases are enzymes that breaks down proteins into smaller components like polypeptides or amino acids.

Introduction

As mentioned earlier, without proper maintenance of the mitochondria, then there will be a decrease in the effectiveness of the mitochondria. This will then also affect the aging for one over time because of the increasing amount of mutations and deletions that may have occurred. Which also damages and stops the translation and folding of proteins. Therefore, there must be something that scientists came up with which is called, Protein quality control (QC) to help gain the proper structure of the protein and proteases that breaks down the proteins that have undergone mutations or misfolds.

There are many genomes for each organelle and these genomes code for thriteen proteins of the Electron Transport Chain. In order to generate biogenesis and mitochondrial DNA, then the mitochondrian needs to carry out reactions by fission and fusion.

Fission will increase the amount of mitochondrial numbers inside the cell before the process of biogenesis. In addition, they are also able to segregate the mutated organelles from degradation. On the other hand, fusion is when organelles mix to have equal amounts of mitochondrial parts.

Foundation of Misfolding

As discussed earlier, there will be a higher risk that proteins will mis-assemble if there are a surmount number of mutations in the mitochondrial DNA (mtDNA). As a result, to reduce proteins from mis-assembling, there must be something that stops the mitochondria from producing errors in its DNA. There was a study that proved this general theory:

• Scientists tested the experiment on mammalian cells. In the experiment they stopped the production of mitochonodrial DNA replication, this resulted in an increase of misfolded proteins.
• This not only could affect the cells in the mitochondria but may also spread into other parts of the body and lead to diseases elsewhere in the body.
• Results also show that because of the mutations that occur in the cells over a long period of time, the proper replication, translation, and folding of proteins will decrease.

Effects of Mitochondrial disease

There are many diseases that can result from the mis-folding of the mitochondrial DNA; many of the diseases are linked to the nerves and the brain. This is because the nerves and brain require a lot of the energy made from mitochondria; a dysfunction in the mitochondria is like cutting off the power source from a powerhouse.

Indications of Mitochondrial Disease

There are many types of symptoms that mitochondrial diseases are known to posses:

• Some of which include vomiting, seizures, heart attack, muscle weakness or loss of muscle coordination, dementia, stroke, blindness, deafness, droopy eyelids, exercise intolerance, poor growth, heart disease, liver disease, kidney disease, and much more.
• Without much of the energy that the mitochondria provides, the patient diagnosed with the disease will be weak and tired. This will not allow the patient to eat, walk, write, or any daily routines.

People who are diagnosed with mitochondrial disease are usually young, around the age of about 20; but this does not limit to who the disease may result in. They usually start out with the symptoms of loss of coordination in the muscles and they feel very weak and they also cannot exercise. People with this disease cannot exercise because their muscle coordination have decreased; however, it is not just exercise that they are not capable of doing, they simply cannot do any activity that requires physical work.

Treatment

Up till now,recent science has not found a complete cure or treatment exactly fit for mitochondrial diseases. However, there are suggestions and ways to help deal with some of the symptoms of the disease.

• Physical therapy is one of the many ways of helping fight mitochondrial disease; it allows the muscles to stretch out which helps counterattack the loss of muscle coordination.
• Another treatment is to take vitamins, which may provide energy for the patients because they are not able to produce enough energy for themselves because of the dysfunction of the mitochondria.
• Recent data also reveals that decreasing the rate of translation might be able to help treat mitochondrial diseases because it will slow down the rate at which the mutation will translate also. Which in turn will slow down the number of mis-assembled proteins that are accumulated in the compartments.

Connection to Biogenesis and Aging

Reactive oxygen species damage the proteins and DNA of the mitochondria while cells are in the process of replication. This superoxide anion is produced in the ETC (electron transport chain) of complex I and III and it can severely damage the protein. Reactive oxygen species are able to damage the cells by either changing the way that proteins fold or simply by just adding in mutations to the DNA.

• Age is a factor that is also affected by mitochondrial dysfunctions; as time passes the damage of DNA accumulated in the genome will decrease an individual's lifespan. This will lead to the decrease in the efficiency of organelles in the body because of the defected proteins that the mitochondria has produced.
  • They ran a test which shows that mice that had the mutations caused by mtDNA were aging faster than normal mice; although they grew up normally, they were definitely losing their capabilities because the rest of their internal compartments were deteriorating so quickly from the mutations in the mitochondrial DNA.

Biogenesis

Complex I of the electron transport chain has many subunits and within these subunits there are or may be mutations and or defects. Depending on the organism, if an individual has the dysfunction then that means there was a mutation or defect and thus this will ruin the whole process of the electron transport chain. As a consequence, this reveals that just one change in one individual nucleic acid such as deletions will greatly change the results of the whole reaction. So it is necessary that efficient QC machinery is needed to take out the bad parts of a protein in order to allow it to fold properly.

QC Machinery

As all know, the mitochondria has four compartments which proteins are made and folded; they are the outer membrane (OM), inner membrane space (IMS), inner membrane (IM) and the matrix. These four compartments work together to create a functional protein and if one part has an error then the whole process is destabilized.

Basically, the QC machinery (quality control machinery) is in control and looks over or examines the proteins that are misfolded in order to find the error that is not allowing the protein to fold properly. So there are chaperones and QC proteases that perform these functions and find the foreign proteins that are covered by the proper proteins.

• A study showed that chaperones in the mitochondria will perform some mechanism in which it will rid or treat the accumulation of misfolded proteins. But if the compartment is full or filled with the maximum amount of defected proteins then this will break down proteins into smaller subunits in which will cause the cell to increase transcription to reproduce the polypeptide. Therefore, this shows that the QC machinery is flexible to change to adapt to any conditions.

Four Compartments of the Mitochondria

There are QC proteases spread out throughout the mitochondria that scan and protect each of the four mitochondrial compartments along with chaperones. Again, they are present in the mitochondria to prevent the accumulation of defected proteins from compiling in each of the compartments.

• The outer membrane contains ubiquitin ligase which is in charge of breaking down mutated proteins that are stuck in the outer membrane. Scientists know that this enzyme is able to do such a thing but does not know how.
• The inner membrane space is supposed to keep the protein from folding as it is being transported from the outer membrane to the innermembrane. It contains the protease HtrA2 which up to recent study does not show any connection for the regulation of breaking down a folded protein. For example, there was a research done on mice in which the mice did not contain the protease HtrA2; this caused the mice to die in a moth from Parkinson's disease which strongly suggests that protease links to biogenesis.
• The next compartment, the inner membrane, is responsible for recognizing which proteins are properly folded and improperly folded. This is done by the i-AAA and the m-AAA proteases; they both work hand in hand with one another to protect the mitochondria from defects. What is unique about these proteases are that they have active sites that face the inner membrane space and the matrix.
• The last compartment of the mitochondrial compartments is the matrix; this compartment is very high in protein concentration and it is processed by mtHSP70 and HSP60. Both these chaperones require energy in order to work because they are ATP dependent. In addition to the chaperones, they also have AAA proteases, Lon and ClpXP. They predicted the function of these chaperones from studies with bacteria because bacteria have the same proteins. Thus, it is not confirmed that these are the same actions that the human body also does. However, in bacteria, it is proven that they will pin point the defected protein and once they do find it then they will destroy it or remove it.

Significance

Why then is all of this important? Researchers continue to do experiments in this field and research on mitochondrial diseases because they want to find out more about this disease. The goal is to be able help cure or treat as many patients that have this disease as possible. And to do this, they must understand the cause of the disease in order to find ways to hinder or prevent the mutations of mtDNA to continue the research. It is also important because this disease leads to other diseases or at least up to recent studies, it is shown that mitochondrial dysfunction results in a decrease in the body;s energy; therefore, it is linked to any cell reactions that require energy. This means that any diseases or illnesses that need energy are going to be affected by the mitochondrial dysfunction. There is also evidence that mitochondrial diseases are connected to cancer and tumors, which range from a big quantity of many different kinds.

• It is a field to be focused on because there are not any treatments or cures designed specifically for this particular disease yet.
• Another point is that there are many people who are born with this dysfunction and research to find a cure would allow millions of people of all ages and especially infants into a better lifestyle. In addition it is like Giving a brand new life to newborn babies that have not experienced anything in this world yet.
• It will provide hope and joy to those suffering from this disease and make children happier to be able to do simple things like run, walk and eat properly like other kids.

Statistics

It is a very important filed to look into because the rate at which people get these diseases are so fast and there is no cure to this disease. Therefore, it is a very essential and crucial topic for researchers to focus on.

• According to the statistics, children will develop mitochondrial disease by the age of ten for every thirty minutes that an infant is born.
• Although less but also significant is that there are one out of two hundred that will soon acquire mitochondrial disease in their life.

This disease is fairly new to the the biological field and not many people study it because it is not diagnosed in every person out there. Also because it is not found in every person out in the world, companies will not give budget to research on this topic. This is why it is important for people to especially research on this topic because not very much is known about this subject; therefore, there will be more breakthroughs looking into this field of study. As a result, it will help many of the patients out there suffering from the mitochondrial disease. Finding a cure or better treatment to this dysfunction may lead to cures in other diseases; such as, Alzheimers, Parkinsons, diabetes, hypertension, osteoporosis, and many more diseases.

Research Experiments

• There was an experiment in which mouses were used to test this experiment. In the experiment, scientists changed one nucleotide in the sequence of the mitochondrial DNA. This experiment showed results in which the mouse became weak because its muscles were losing coordination. It also showed that the health of the mouse was slowly decreasing and ultimately led to heart disease.
• A drug was used to increase thinking and function for patients with Alzheimer's disease; this is done from stabilizing the mitochondria.
• Another link to mitochondrial disease is that it may result in cancer. This is because the signaling must occur inside a cell between the nucleus and the mitochondria. Therefore, if the mitochondria is not working because of the dysfunction then this will lead to cancer.
• Researchers also found that in patients with diabetes, the mitochondria efficiency is decreased. This shows that the mitochondria causes patients to obtain high sugar levels at some degree.

Reference

Baker, Brooke M., and Cole M. Haynes. "Mitochondrial Protein Quality Control during Biogenesis and Aging." (n.d.): n. pag. Rpt. in New York: Sloan-Kettering Institute, Cell Biology Program.

"Mitochondrial Disease Causes, Symptoms, Diagnosis, and Treatment on MedicineNet.com." MedicineNet. Government, n.d. Web. 06 Dec. 2012

"Mitochondrial Disease." United Mitochondrial Disease Foundation, n.d. Web. 6 Dec. 2012.