Alert in the Cell Power Plant

30. September 2010

Mitochondria are a whole lot more than just energy manufacturers of the cell. They are also the alarm system for the immune response. With the knowledge about their importance for systemic inflammations the therapeutic opportunities increase as well.

Actually it’s a prime example for the successful company merger what you find inside every eukaryote cell. It started with a careful scanning – when a proteobacterium implanted itself in a nucleated cell. This again kept the useful parts for energy production of the host to itself and got rid of the rest. The intruder became an organelle of higher developed beings, the mitochondrion.

They still have a marked own life, those particles tightly folded inwards in the cell, for example an own DNA (mtDNA). Mitochondria are more than just a power plant. They are also an armory providing their arsenal whenever a danger threatens from the outside. With their help, the cells starts its suicide program if there is now way out. They play an important role in inflammations and they are cause for a disease whenever the cell loses control over its subjects.

Released mtDNA causes cell alarm

In spring this year, an article in Nature illustrated how mitochondria influence the inflammation for example in a sepsis significantly. Carl Hauser and his team in Boston showed that patients with a trauma release mitochondria DNA. Other typical components of this energy organelle as well like peptides with a terminal formyl-residue affect the congenital immune system as “DAMP – Danger Associated-Molecular-Pattern” – as the alarm siren of the body. The called-for guards are neutrophilic granulocytes sending more inflammation mediators on their journey, among others collagenase which allows the immune system to enter the peripheral tissues.

When the researchers injected mitochondrial DNA intravenously in rats, the rodents soon reacted with damages in their lungs like they appear at times with an infection. The researchers found large quantities of neutrophiles. Pro-inflammatory cytokines like IL-6 or TNF-alfa originate from this source. Also without the invasion of micro-organisms, the physician sometimes discovers a SIRS (=Systemic Inflammatory Response Syndrome). The symptoms are often very similar to sepsis, but until recently, the connections remained not understood. The similarity between bacterial and mitochondrial antigens could be a key to clarification. Neutrophiles possess TLR-9-receptors fitting in mitochondria- as well as bacteria-DNA. The same applies for formyl-peptide receptors of the innate immune system. The formic acid residue in peptides is also typical for bacteria.

The apoptosis, the signal chain for the progammed cell death, all merge at the mitochondria. Bcl-2 is one of the most important known controlling elements of apoptosis and inhibits biochemical processes at the mitochondria-membranes.

Cancer cells disarm their own armory

More and more cancer researchers are interested in such activities. If they succeeded to get tumor cells into apoptosis on time, they would have found an appropriate tool against the uncontrolled mass reproduction of cells. Cancer stem cells – as known by now – are lacking reactive oxygen species (ROS). They develop more or less automatically during oxidative energy production but are toxic for the cell. Perhaps the tumor cell protects itself against its own destruction by cutting off its alarm system and decreasing transportation of hazardous goods. According to specialists this is exactly where an effective fight against tumors could start.

Own genetic code protects against radicals

The cell protects itself against the dangers of toxic substances with its own mitochondria genetic code. Here some base-triplets code for other amino acids than inside the cell nucleus. Two years ago, researchers at the Mainz University decoded the backgrounds of this difference. Methionine accumulates more frequently in the mitochondria proteins than anywhere else. Thus the changed peptides are less sensitive against the ROS attacks. “This is particularly important in the mitochondria since a high oxygen turnover results nearly always in the production of free radicals”, says Bernd Moosmann, head of the Mainz working group.

Defects in the mitochondria functions cause about 150 diseases known so far. The most relevant are for example ‘Leber’s heredity optic neuropathy, often combined with cardiac arrhythmia, the Kearns-Sayre syndrome, which is a paralysis of the eye lids, but also morbus Parkinson, Alzheimer disease and epilepsy are diseases researcher connect with mitochondria.

Targets in the fight against parasites and systemic inflammations

Results like those of the Boston working group put proteins and DNA of mitochondria more and more into the center point of view in medicine. The well-known oncologist Bert Vogelstein published his results in the same edition of ‘Nature’ as Hauser. According to those, the mitochondria of healthy cells contain a very heterogenic mixture of mitochondrial DNA with different mutations varying from tissue to tissue.

Eukaryotic human parasites most likely are by far more different from the human mtDNA. The changed components of the parasitic respiratory chain complex thus are a potential target for new chemo-therapeutics. The cell organelles for sure are catching even more attention due to their role in systemic inflammations during sepsis or after traumas. The high mortality rate of these diseases leaves plenty of room for innovative therapies.

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