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Elucidation of the role of the MICOS complex in signal transduction from mitocondrial DNA nucleoids

Hellman, Michael LU (2015) KBK820 20151
Pure and Applied Biochemistry
Abstract
The MICOS complex protein MicF has recently been identified to play a vital role in the mitochondrial DNA inheritance checkpoint, a control system that halts cell cycle progression in cells lacking mitochondrial DNA (mtDNA). We show in this report that another member of the complex, MicA, also plays an important role in the mtDNA inheritance checkpoint as its deletion led to cell cycle progression in cells lacking mtDNA (Rho0 cells). We observed that deletion of MicA, just like deletion of MicF, led to aggregated mtDNA in addition to the severe defects in the architecture of the inner mitochondrial membrane observed in all MICOS deletion strains. These findings lead us to believe that MicA and MicF might be involved in the signal... (More)
The MICOS complex protein MicF has recently been identified to play a vital role in the mitochondrial DNA inheritance checkpoint, a control system that halts cell cycle progression in cells lacking mitochondrial DNA (mtDNA). We show in this report that another member of the complex, MicA, also plays an important role in the mtDNA inheritance checkpoint as its deletion led to cell cycle progression in cells lacking mtDNA (Rho0 cells). We observed that deletion of MicA, just like deletion of MicF, led to aggregated mtDNA in addition to the severe defects in the architecture of the inner mitochondrial membrane observed in all MICOS deletion strains. These findings lead us to believe that MicA and MicF might be involved in the signal transduction from mtDNA across the mitochondrial membranes and that their deletion leads to loss of contact sites between the membranes and thereby renders transduction across the membranes impossible. (Less)
Popular Abstract
Defect in a mitochondrial protein opens up the door for a multitude of severe diseases

Severe diseases such as Alzheimer’s Disease, Diabetes type II and Cancer have all been linked to one common source – unhealthy mitochondria. Mitochondria stay healthy (or self destruct if they can not) and thereby avoid these diseases with the help of its own quality control mechanism. Defects in a recently discovered protein complex called the MICOS complex have now been shown to override this mechanism, thereby opening up for these terrible diseases.

Alzheimer’s disease is a sad and incurable disease, from which according to estimations by the World Health Organization (WHO) around 35.6 million people were suffering from in 2012. Unfortunately,... (More)
Defect in a mitochondrial protein opens up the door for a multitude of severe diseases

Severe diseases such as Alzheimer’s Disease, Diabetes type II and Cancer have all been linked to one common source – unhealthy mitochondria. Mitochondria stay healthy (or self destruct if they can not) and thereby avoid these diseases with the help of its own quality control mechanism. Defects in a recently discovered protein complex called the MICOS complex have now been shown to override this mechanism, thereby opening up for these terrible diseases.

Alzheimer’s disease is a sad and incurable disease, from which according to estimations by the World Health Organization (WHO) around 35.6 million people were suffering from in 2012. Unfortunately, it is estimated that these numbers will be more than tripled (115.4 million) by 2050. At the same time, the amount of people suffering from metabolic diseases such as diabetes type II is continually growing. According to WHO, an estimation of 9% above 18 years of age are suffering from diabetes, out of which 90% of the cases are diabetes type II. The fact that these numbers are huge, and even worse that they are rapidly increasing, speaks for how great the urge for getting to the root of the problem is. Finding this root to the diseases by mapping out what goes wrong in the mitochondria is probably the best way to start the search for a solution to the problem.

The mitochondrion has its own DNA, called mtDNA. When the mtDNA is damaged or absent in the mitochondrion, signals are sent out to the cell nucleus that the mtDNA needs to be repaired, and if that is not possible that the cell should be killed. A mitochondrial protein complex called the MICOS complex has recently been shown to be involved in sending this signal on from the mitochondrion to the cell nucleus. How the proteins of the complex are involved has however remained unknown until now. Mapping out this unknown area is an important step in understanding how many severe diseases arise and how they can be prevented. Doing that by characterizing the role of the MICOS complex in the quality control mechanism has been the focus of my project.

Mitochondria consist of two membranes. The outer membrane has a relatively smooth oval shape. The inner membrane however has a different architecture, and is formed more like a switchback road in the Alps, or like hairpin turns. The MICOS complex is located to this inner membrane. To get a better picture of what roles the 6 proteins of the MICOS complex have these proteins were deleted one by one in yeast cells. Yeast cells are much easier to work with than human cells, but are similar enough to get a good clue of the situation in humans.

The effects of the protein knockouts were studied by microscopy and by looking at their growth rate as well as how they multiply. We saw that all of the proteins of the MICOS complex were important for the specific architecture of the inner membrane that is seen in mitochondria. This architecture might be important for the mitochondria to function optimally, but it does not affect the mentioned quality control mechanism.

Further examination however showed that especially two of the MICOS proteins play very important roles not only for the mitochondrial architecture, but also for keeping the mtDNA healthy and for the quality control mechanism to function properly. It was seen that when any one of these proteins were knocked out, even cells that had no mtDNA continued to grow and divide even though they should have signaled for self destruction. Our conclusion drawn from this observation is that these proteins are vital for a functioning quality control mechanism by making sure that signals for self-destruction from inside the mitochondria to the outside can be sent when needed.

In summary, our results showed that problems with the two most important MICOS proteins open up the door for a lot of severe diseases. Further research can hopefully figure out how problems with these proteins arise and how to avoid it, leading to prevention of tragic diseases for millions of people around the world. (Less)
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author
Hellman, Michael LU
supervisor
organization
course
KBK820 20151
year
type
H2 - Master's Degree (Two Years)
subject
keywords
tillämpad biokemi, applied biochemistry
language
English
id
8167025
date added to LUP
2016-01-13 15:23:44
date last changed
2016-01-13 15:23:44
@misc{8167025,
  abstract     = {The MICOS complex protein MicF has recently been identified to play a vital role in the mitochondrial DNA inheritance checkpoint, a control system that halts cell cycle progression in cells lacking mitochondrial DNA (mtDNA). We show in this report that another member of the complex, MicA, also plays an important role in the mtDNA inheritance checkpoint as its deletion led to cell cycle progression in cells lacking mtDNA (Rho0 cells). We observed that deletion of MicA, just like deletion of MicF, led to aggregated mtDNA in addition to the severe defects in the architecture of the inner mitochondrial membrane observed in all MICOS deletion strains. These findings lead us to believe that MicA and MicF might be involved in the signal transduction from mtDNA across the mitochondrial membranes and that their deletion leads to loss of contact sites between the membranes and thereby renders transduction across the membranes impossible.},
  author       = {Hellman, Michael},
  keyword      = {tillämpad biokemi,applied biochemistry},
  language     = {eng},
  note         = {Student Paper},
  title        = {Elucidation of the role of the MICOS complex in signal transduction from mitocondrial DNA nucleoids},
  year         = {2015},
}