Abstract
Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS.
Highlights
IntroductionMitochondria are essential eukaryotic organelles harboring 1000–2000 different proteins
Mitochondria are essential eukaryotic organelles harboring 1000–2000 different proteins.Approximately 99% of the total mitochondrial proteins are encoded by nuclear DNA, synthesized as precursors in the cytosol, and imported into mitochondria via elaborate transport machineries
Tim proteins is tightly coupled with their oxidative protein folding, which can be divided into four sequential steps: (i) In the cytosol the precursor proteins are kept in a reduced and unfolded form by cytosolic factors [13,14]; (ii) mitochondrial import of the reduced precursor proteins through the the outer membrane (TOM)
Summary
Mitochondria are essential eukaryotic organelles harboring 1000–2000 different proteins. Tim proteins is tightly coupled with their oxidative protein folding, which can be divided into four sequential steps: (i) In the cytosol the precursor proteins are kept in a reduced and unfolded form by cytosolic factors [13,14]; (ii) mitochondrial import of the reduced precursor proteins through the TOM complex [15]; (iii) oxidative protein folding in the IMS regulated by the mitochondrial import and assembly (MIA) pathway [16,17,18]; (iv) assembly of the oxidized, partially folded proteins into hexameric small Tim complexes [19,20] All of these steps depend on the redox state of the conserved cysteine residues—while only reduced unfolded proteins can be imported into mitochondria, protein folding and complex formation requires disulfide bond formation. We will discuss how the small Tim hexameric complex is assembled, and the mechanism by which this complex might perform its chaperone function
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