Cytosolic redox components regulate protein homeostasis via additional localisation in the mitochondrial intermembrane space

Abstract

Oxidative protein folding is confined to the bacterial periplasm, endoplasmic reticulum and the mitochondrial intermembrane space. Maintaining a redox balance requires the presence of reductive pathways. The major thiol-reducing pathways engage the thioredoxin and the glutaredoxin systems which are involved in removal of oxidants, protein proofreading and folding. Alterations in redox balance likely affect the flux of these redox pathways and are related to ageing and diseases such as neurodegenerative disorders and cancer. Here, we first review the well-studied oxidative and reductive processes in the bacterial periplasm and the endoplasmic reticulum, and then discuss the less understood process in the mitochondrial intermembrane space, highlighting its importance for the proper function of the cell.

Keywords: mitochondria; oxidative folding; reductive pathways.

Figure 1

The three main protein import pathways into mitochondria. (A) The MIA pathway precursors cross the OM membrane via the TOM channel in a reduced state. Once in the IMS, they interact with Mia40 which serves as receptor and oxidoreductase and promotes the insertion of disulphide bonds into the proteins. (B) The presequence pathway precursors are translocated across the TOM channel to the TIM23 complex. They contain a positively charged presequence that helps them cross the IM in a membrane potential (ΔΨ)‐dependent manner. These proteins are then either fully translocated to the matrix or transferred to the IM and the presequence is cleaved off. (C) The carrier pathway precursors are first delivered to the Tom70 receptor by cytosolic chaperones. In the IMS, the small Tim proteins help them to interact with the TIM22 complex for their insertion into the IM.

Figure 2

Redox processes in the bacterial periplasm, endoplasmic reticulum and mitochondrial intermembrane space. (A) Redox processes taking place in the bacterial periplasm. Oxidation of proteins by DsbA, which is in turn oxidised by the membrane protein DsbB (left). Electron flux from the cytosolic Trx system onto DsbD, then to DsbC and finally to the protein (right). (B) Redox processes in the ER. Protein oxidation by PDI and reduced PDI recycling by e⁻ transfer onto Ero1 (left). Protein reduction/isomerisation pathway by PDI reduced by either GSH or NADPH (right). (C) Redox processes in the IMS. Protein import mediated by the Mia40 oxidation of protein precursors. Mia40 is kept in an oxidised state by Erv1, or alternatively by Gpx3. This process may be facilitated by Hot13 which is proposed to keep Mia40 in its reduced state ((left). The Trx and Grx systems were recently localised in the IMS. It is likely that these reductive systems play a role in Mia40 reduction to keep the oxidised/reduced overall state of Mia40 necessary for its import function and also that they play a role in protein isomerisation (right).

Figure 3

The two main thiol‐reductive systems. Both the thioredoxin and the glutaredoxin system use the NADPH produced by the pentose phosphate pathway enzyme G6PD as their final electron donor. (A) The thioredoxin system electron flux starts from NADPH which reduces the thioredoxin reductase, which then reduces the thioredoxin protein. Finally, the thioredoxin protein transfers this e⁻ to its substrates. (B) The glutaredoxin system follows a similar e⁻ flux with an extra step involving glutathione reductase e⁻ transfer onto glutathione, and subsequently, from glutathione onto glutaredoxin and then to glutaredoxin substrates.