Mitochondrial Mechanisms of Disease: Lessons from Extremophiles

Christos Chinopoulos and his team of scientists from Semmelweis University have been investigating the intriguing resistance of certain extremophile crustaceans to the cell death pathway that is linked to many of the currently incurable neurodegenerative diseases.

Neurodegenerative disease is an umbrella term for a range of conditions that primarily affect the neurons in the human brain. It includes Parkinson’s, Alzheimer’s and Huntington’s disease among others. They are incurable and debilitating conditions that result in the progressive degeneration or death of nerve cells, leading to problems with movement and mental functioning.

However, it has recently been opined that many of these diseases may have similarities on a sub-cellular level, which could mean that possible therapeutic solutions could offer hope for many of them simultaneously. Chinopoulos explains how he became interested in the topic.

“When I became a member of the research staff involved in neurochemistry back in 1994, the main line of research led by Prof. Adam-Vizi was the role of oxidative stress on neurodegenerative diseases, specifically Parkinson’s disease. The topic relied heavily upon investigating mitochondrial functions, because mitochondria are a major source of reactive oxygen species (which are thought to underlie the degenerative processes that occur in Parkinson’s) as well as being a target for them.

It was at around this time that the scientific community began to realise that mitochondrial dysfunction is a common denominator for many of the currently untreatable neurodegenerative diseases – a hypothesis that has been repeatedly vindicated over the past two decades.”

This line of work eventually led Chinopoulos to Baltimore, where he studied mitochondriology under Gary Fiskum, a world-leader in the subject. He was eventually drawn to work on the ‘holy-grail’ of the subject – the identification of the components of the permeability transition pore (PTP). This is basically an assembly of unknown proteins that cause the disruption of mitochondrial integrity and initiate cell death, and can be activated by a number of different conditions, and it is what Chinopoulos and his team have been trying to pinpoint for the last decade.

When Steven Hand and his group reported in 2005 that the crustacean Artemia franciscana lacked the permeability transition in the face of a profound calcium storage, Chinopoulos noted that these organisms may be the key to their research. “We came to see that an excellent strategy for finding out the proteomic components responsible for PTP would be to investigate the mitochondria of organisms that do not exhibit PTP, and thus do not experience this particular cell death pathway. What is it that these organisms have (or lack) that make them so resistant?”

The team’s methodology involved preparing the mitochondria of specific marine crustacean species and performing a number of functional tests on them, such as biochemical assays and the sequencing of the mRNA of proteins of interest. They repeated the same process using various organisms, making comparisons from a number of different areas of the phylogenetic tree. This allowed them to assess what proteins were different and in what way they could be mediating the mitochondrial death pathway.

“We are narrowing our search down to one particular mitochondrial protein, which for the most part has a very basic function, but is also known to have other so-called ‘moonlighting’ abilities, meaning that it can exhibit several other functions as well. One of these other functions is the modulation of pore opening in mitochondria, which mediates their demise, that in turn leads to the death of the cell itself.”

“We have found that this particular protein in some crustacean species that lack the cell death pathway has some domains that differ from those in the mammalian homologues. So what we are doing now is taking mammalian and yeast cell lines in which we have removed this protein, and trying to introduce the crustacean homologue from the organisms in which the cell death pathway is not present. We will hopefully be able to see in these new cell lines that they have gained some resistance to this death pathway.”

The ramifications of this research could well prove to be extremely important. If they are able to identify a protein that is critical in mediating death pathways in the mammalian homologues, then theoretically it will mean that a drug could be devised to target this particular protein so that it loses that part of its functionality, therefore alleviating patients against the cell death pathways that are known to occur in a number of different diseases. This approach of trying to understand the reason why mitochondria are a common denominator in so many diseases could lead to a whole range of new treatments for many of them.

Other Research

Chinopoulos and his team are not only confined to this particular subject – for instance, another area they have been studying has been the citric acid cycle, and how it is not actually a cycle at all. “If you write out on paper a list of substances being created and consumed, it will look like a cycle, but this is not what happens in reality. We want to understand how it really operates under conditions of mitochondrial stress, which we can induce using targeting inhibitors of the mitochondrial transport chain”.

Also being studied is cyclophilin D, another protein that is involved in mitochondrial dysfunction. There is currently a drug available that inhibits this protein that is used for treating patients who have undergone a transplant and require immunosuppresssion. There are preliminary experiments by others showing excellent levels of protection, and so the group from Semmelweis are now trying to understand the role that this protein plays in cell and organ death.

Click here to contact Christos Chinopoulos.

Published: Monday, 17th October 2011