Walter Neupert Talk

Tuesday and Wednesday Dr Neupert was here at the medical school. The topic of his two seminars was mitos.

It is amazing how many protein shuttling mechanisms there are in mitos. Mitos only make about a dozen proteins from their own DNA, the rest are synthesized from nuclear genes. These nuclear derived gene products have to be imported into the mitos and this is where all the protein transport comes in. There's the TIM and TOM complexes to shuttle proteins from the cytoplasm into the intermembrane space and matrix, the TOB complex the Oxa transport system, the stop transfer system all working to get membrane proteins inserted into the inner and outer mitochondrial membrane. And yes the presence of all these protein translocation systems only makes sense when you consider where mitos came from.

So what are mitos good for?

As usual most of the genetic analysis has been performed in yeast. So the good news is that mitos are essential, the strange news (well not so strange if you think about yeast) oxidative phosphorylation (i.e. the conversion of carbohydrates and oxygen to CO2, H2O energy and oxydative potential) is not essential for life. Yes yeast can grow anaerobically. So why are mitos essential. Well although you can knockout the oxphos system there are three mito components that are essential for life:

1) Mito transport systems (TIM, TOM, TOB, Oxa complexes).
2) Mito chaperones that help proteins that are imported to the mitos fold and also help drive import.
3) Genes involved in sulfur ion complex formation.

It turns out that mitos have proteins in heir inner membrane space that complex to various metal ions such as zinc and copper by the action of proteins with four cysteine residues. These proteins are imported from the cytoplasm as unfolded substrates, and are folded in the inner membrane space by undergoing an oxidation and reduction cycle where the cysteins form disulfide linkages that are subsequently reduced. This cycle is is catalyzed by oxidizing and reducing proteins in the inner membrane space. This is what is essential. Since mitos can perform this oxidative reduction cycle (which can't happen in the cytosol) it may be the only place in the cell where these metal chelating proteins can be properly folded. Interestingly, gram negative bacteria (i.e. bacteria with a periplasmic space) also have oxidative reductive proteins in the periplasmic space that act to exchange disulfide bonds and promote protein folding, so in this way the cellular function was conserved although to my knowledge the actual oxidative and reducing enzymes may not be the same. Also proteins in the mitos end up reduced while proteins in the periplasmic space of bacteria end up oxidized - so again it is a little different between the two systems.

So how wide spread is this sulfur ion business? It turns out that certain eukaryotic protists have very minimal remnant mitos that have lost most of their functions. Despite the fact that these mitos have no DNA and are minuscule bilayered sacs, they still contain (protein wise) the three systems mentioned above ... the mito import proteins, mito chaperones and sulfur ion complex proteins. So even in organisms that got rid of every mito function, they couldn't dispense with the sulfur ion system.

What are these sulfur ion clusters good for? Well beside scavenging metal ions, it remains unclear. Any thoughts out there?