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13.05.2009

Mitochondria – making the impossible possible

The transport of proteins across the two mitochondrial membranes is a very complex process. Huge molecular machines recognise the precursor proteins which are formed inside the cell and which are destined for the energy power stations of the cells. Some of these substances pass the outer and the inner membrane, some of them remain in the intermembrane area. How does the sorting of the molecules work? Five years ago, molecular biologist Dr. Agnieszka Chacinska and her team at the University of Freiburg discovered a new molecular system that sorts the molecules and that functions on the basis of a process that is not really possible.

Disulphide bridges are chemical bindings between two sulphur atoms. The researchers led by Dr. Agnieszka Chacinska from the Institute for Biochemistry and Molecular Biology at the University of Freiburg were surprised to discover these bridges between the two membranes of the mitochondria. Normally, this cellular compartment is reductive; many molecules have to accept additional electrons. The researchers initially thought that disulphide bridges could only form in an oxidative environment, where electrons are withdrawn from a substance. In addition, the researchers were also interested in gaining insights into how the disulphide bridges formed. This is a process that is known as protein sorting. Chacinska and her team from the Institute for Biochemistry and Molecular Biology (Director: Prof. Dr. Nikolaus Pfanner) originally investigated how proteins managed to enter the mitochondria, where they are separated into clearly distinct areas. “Our findings were thus of great interest for two reasons,” said Chacinska.

A molecular shelter

Inner and outer mitochondrial membrane: the ways in which precursor proteins that are destined for specific mitochondrial areas are very complex. The proteins Mia40 and Erv1 are located between the membranes and sort the intermembrane proteins.new window
Inner and outer mitochondrial membrane: the ways in which precursor proteins that are destined for specific mitochondrial areas are very complex. The proteins Mia40 and Erv1 are located between the membranes and sort the intermembrane proteins. Inner and outer mitochondrial membrane: the ways in which precursor proteins that are destined for specific mitochondrial areas are very complex. The proteins Mia40 and Erv1 are located between the membranes and sort the intermembrane proteins. (© Dr. Agnieszka Chacinska)
Mitochondria have important tasks. They are not only used to generate energy. They also have regulatory functions, because certain enzymes in these organelles can induce programmed cell death to remove old or damaged cells. The mitochondria require many proteins to do this, but they are unable to produce all of them. Traditional protein importation involves huge molecular complexes in the outer membrane. These translocases recognise certain sequences on the protein precursors destined to enter the mitochondria and transport them across the outer membrane. The protein precursors are transported further on to the translocases located in the inner membrane, which have similar functions to those located in the outer membrane.

But what happens with the substances that have to remain in the intermembrane space, for example chaperones of the family of Tim proteins, which help other proteins in the intermembrane space to fold correctly?

In 2004, Chacinska and her colleagues in Prof. Pfanner’s department discovered the enzyme Mia40, which picks up the precursor proteins of the Tim chaperones from the outer membrane. Mia40 recognises a specific signal, which is characteristic of proteins that have to remain in the intermembrane space. This is a short amino acid sequence attached to the sulphur-containing amino acid cysteine. Mia40, which is anchored in the inner mitochondrial membrane, interacts with the Tim proteins via disulphide bonds that are formed by oxidising sulphur (electron withdrawal). Mia40 cannot do this on its own. Once in a reduced state (uptake of electrons), Mia40 is oxidised by the enzyme Erv1, a sulfhydryl oxidase. This step is necessary, because otherwise Mia40 would accumulate and remain inactive. In addition, Erv1 builds a kind of shelter, together with Mia40,” said Chacinska. In this shelter, another connection can be established between the interior of the protein and two cysteines.

Additional helpers? Radicals?

The photo shows the intermediary products of Tim9 and related precursors proteins (coloured spots) during their import into the mitochondria. These proteins were separated on a gel according to their relative masses.
The photo shows the intermediary products of Tim9 and related precursor proteins (coloured spots) during their import into the mitochondria. These proteins were separated on a gel according to their relative masses.  (© Judith M. Müller and Dr. Agnieszka Chacinska)

"Once the ternary complex consisting of Mia40, Erv1 and the protein falls apart, this means that two new disulphide bridges have been inserted in the protein, enabling it to fold and remain in the intermembrane space," said Chacinska. "We believe that the individual steps of this rather complex process would not be possible in the reductive environment of the intermembrane space without the shelter formed by Erv1 and Mia40." The intermediary products would most likely be too instable and would quickly be reassembled. 

So far, Chacinska and her team have only tested their findings in yeast cells. But in future, they hope to find out whether other proteins that remain in the intermembrane space are processed in a similar way. In addition: Mia40 and Erv1 are absolutely vital for cells. But are there any further substances that maybe regulate this process? And how about this mechanism in the cells of higher organisms?

And another question needs to be answered. The disulphide bridges are the result of chemical reactions in which electrons jump from one molecule to another. Such reactions always produce reactive oxygen molecules as side products. These radicals may cause considerable damage to cells. Ageing and many neurodegenerative diseases are associated with radicals produced in the mitochondria. "Does the system consisting of Mia40 and Erv1 play a role in such undesired effects?" asks Chacinska. "We hope that we will also be able to answer these questions in the future."

A contribution from:
Logo BioRegion Freiburg
mn - 13.05.2009
© BIOPRO Baden-Württemberg GmbH

Further information:
Agnieszka Chacinska
Institute for Biochemistry and Molecular Biology
Stefan-Meier-Straße 17
D-79104 Freiburg
Tel.: +49 (0)761/203 -5245,
Fax: +49 (0)761/203 -5261
E-mail: Agnieszka.Chacinsk(at)biochemie.uni-freiburg.de

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