Cytosolic thioredoxin system facilitates the import of mitochondrial small Tim proteins

Durigon, Romina; Wang, Qi; Pavia, Efrain Ceh; Grant, Chris M.; Lu, Hui

doi:10.1038/embor.2012.116

Cited by 35 publications

(23 citation statements)

References 28 publications

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“…Other studies have shown the importance of redox systems for the import of mitochondrial proteins into the IMS. Loss of yeast thioredoxins leads to reduced import rates and accumulation of oxidized unimported pre-proteins (Durigon et al., 2012). However, the IMS localization of thioredoxin could provide an alternative explanation, since Trx1 may be responsible for maintaining the redox environment in the IMS, as well as providing the reducing power for Gpx3.…”

Section: Discussionmentioning

confidence: 99%

Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding

et al. 2017

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SummaryThiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2 sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis.

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Section: Discussionmentioning

confidence: 99%

Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding

et al. 2017

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“…A second model is based on our recent finding that the cytosolic Trx system facilitates the import of mitochondrial small Tim proteins [14]. Thioredoxins and glutaredoxins (Grx) are ubiquitous oxidoreductases in charge of thiol regulation and oxidative stress defense.…”

Section: Keeping the Precursor Protein Reduced And Unfolded In Thementioning

confidence: 99%

“…Durigon et al . [14] recently showed that a Δ trx1trx2 double deletion mutant has a strong growth defect under respiratory conditions. The mutant strain also has lower mitochondrial levels of the small Tim proteins.…”

Section: Keeping the Precursor Protein Reduced And Unfolded In Thementioning

confidence: 99%

“…Furthermore, an efficient disulfide bond transfer reaction was reconstituted using purified Tim10 and the Trx1 system. In vitro assays have also shown that Trx1 is capable of reducing the partially oxidized, one-disulfide-bonded intermediates of Tim10, while the fully oxidized protein was Trx-resistant [14]. These results suggest that the Trx system counterbalances the oxidative folding in the cytosol by reducing any early folding intermediates, which were shown to be import-incompetent as well [22].…”

Section: Keeping the Precursor Protein Reduced And Unfolded In Thementioning

confidence: 99%

“…A unique feature for most of the IMS proteins is that their post-translational import is regulated by their cysteine redox state [11,12]. The biogenesis of the small 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 [16–18]; (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.…”

Section: Introductionmentioning

confidence: 99%

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Folding and Biogenesis of Mitochondrial Small Tim Proteins

Ceh-Pavia

Spiller

2013

IJMS

Self Cite

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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.

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

Cardenas-Rodriguez

Tokatlidis

2017

FEBS Letters

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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.

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Cytosolic thioredoxin system facilitates the import of mitochondrial small Tim proteins

Cited by 35 publications

References 28 publications

Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding

Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding

Folding and Biogenesis of Mitochondrial Small Tim Proteins

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

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