Abstract
Mitochondria have a central role in cellular metabolism; they are responsible for the biosynthesis of amino acids, lipids, iron–sulphur clusters and regulate apoptosis. About 99% of mitochondrial proteins are encoded by nuclear genes, so the biogenesis of mitochondria heavily depends on protein import pathways into the organelle. An intricate system of well-studied import machinery facilitates the import of mitochondrial proteins. In addition, folding of the newly synthesized proteins takes place in a busy environment. A system of folding helper proteins, molecular chaperones and co-chaperones, are present to maintain proper conformation and thus avoid protein aggregation and premature damage. The components of the import machinery are well characterised, but the targeting signals and how they are recognised and decoded remains in some cases unclear. Here we provide some detail on the types of targeting signals involved in the protein import process. Furthermore, we discuss the very elaborate chaperone systems of the intermembrane space that are needed to overcome the particular challenges for the folding process in this compartment. The mechanisms that sustain productive folding in the face of aggregation and damage in mitochondria are critical components of the stress response and play an important role in cell homeostasis.
Highlights
Mitochondria are subcellular organelles that are critically important for cell physiology and development
A very substantial part of the intermembrane space proteins contain cysteine motifs – either CX3C or CX9C – which later become oxidised, forming strong disulphide bonds necessary for intermembrane space protein maturation. This discovery was based upon the presence of internal disulphides found within the TIM intermembrane space chaperones.[36,52]. This speci c pathway is known as the MIA pathway (Fig. 2), as preproteins involved in this pathway primarily interact with the oxidoreductase protein Mia40.48 In this interaction, Mia[40] is bound to the inner membrane, leaving its C-terminus accessible to the intermembrane space; it is at this C-terminus where substrates interact with the oxidoreductase protein.[10]
Mitochondria have developed multiple import pathways to accommodate the import of the different types of proteins needed for mitochondrial function
Summary
Mitochondria are subcellular organelles that are critically important for cell physiology and development. Jamie completed a Master's by Research in the Tokatlidis group investigating the oxidative folding pathways in the mitochondrial intermembrane space. 10% are annotated as outer membrane proteins whilst only 5% are designated as intermembrane space (IMS) proteins.[7] Despite making up a small proportion of the mitochondrial proteome, proteins of the outer membrane and the IMS play a crucial role in the numerous functions of the mitochondrion. These include, apoptosis, phospholipid biosynthesis, haem biosynthesis and critical communications with the cytosol and other organelles. We discuss the various chaperone systems in the IMS which are critical for sustaining an efficient folding environment in this compartment
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