Kinetic control by limiting glutaredoxin amounts enables thiol oxidation in the reducing mitochondrial intermembrane space

Kojer, Kerstin; Peleh, Valentina; Calabrese, Gaetano; Herrmann, Johannes M.; Riemer, Jan

doi:10.1091/mbc.e14-10-1422

Cited by 64 publications

(70 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In view of the general lack of substrate specificity observed in this work, all proteins transiting the IMS en route to their final location are potential substrates of the Mia40/lfALR system. However oxidation might be prevented by efficient sequestration during interactions with translocases [12, 13, 59] or chaperones [59, 60], or might be reversed via IMS-resident reductase sytems [23, 61–63]. In terms of an expanding role for the Mia40/lfALR system, it is interesting to note that a mitochondrial matrix protein Mrp10 contains two disulfide bonds that are inserted during transit through the IMS [34].…”

Section: Discussionmentioning

confidence: 99%

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Hudson

Thorpe

2015

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Mia40 participates in oxidative protein folding within the mitochondrial intermembrane space (IMS) by mediating the transfer of reducing equivalents from client proteins to FAD-linked oxidoreductases of the Erv1 family (lfALR in mammals). Here we investigate the specificity of the human Mia40/lfALR system towards non-cognate unfolded protein substrates to assess whether the efficient introduction of disulfides requires a particular amino acid sequence context or the presence of an IMS targeting signal. Reduced pancreatic ribonuclease A (rRNase), avian lysozyme, and riboflavin binding protein are all competent substrates of the Mia40/lfALR system, although they lack those sequence features previously thought to direct disulfide bond formation in cognate IMS substrates. The oxidation of rRNase by Mia40 does not limit overall turnover of unfolded substrate by the Mia40/lfALR system. Mia40 is an ineffective protein disulfide isomerase when its ability to restore enzymatic activity from scrambled RNase is compared to that of protein disulfide isomerase. Mia40’s ability to bind amphipathic peptides is evident by avid binding to the isolated B-chain during the insulin reductase assay. In aggregate these data suggest that the Mia40/lfALR system has a broad sequence specificity and that potential substrates may be protected from adventitious oxidation by kinetic sequestration within the mitochondrial IMS.

show abstract

Section: Discussionmentioning

confidence: 99%

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Hudson

Thorpe

2015

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

show abstract

“…88 Pioneering work from the Herrmann group established that the import and folding of many proteins within this mitochondrial compartment, including a suite of COX assembly factors with canonical twin Cx 9 C motifs, requires a disulphide relay system 89, 90 that bares remarkable similarity to the one operating in the ER. 91 Mitochondria are also major sources of superoxide anion and hydrogen peroxide, and a number of resident enzymes are dedicated to the conversion and consumption of these ROS.…”

Section: Mitochondria Redox Regulation and Control Of Copper Homeostmentioning

confidence: 99%

The mitochondrion: a central architect of copper homeostasis

2017

View full text Add to dashboard Cite

All known eukaryotes require copper for their development and survival. The essentiality of copper reflects its widespread use as a co-factor in conserved enzymes that catalyze biochemical reactions critical to energy production, free radical detoxification, collagen deposition, neurotransmitter biosynthesis and iron homeostasis. However, the prioritized use of copper poses an organism with a considerable challenge because, in its unbound form, copper can potentiate free radical production and displace iron-sulphur clusters to disrupt protein function. Protective mechanisms therefore evolved to mitigate this challenge and tightly regulate the acquisition, trafficking and storage of copper such that the metal ion is rarely found in its free form in the cell. Findings by a number of groups over the last ten years emphasize that this regulatory framework forms the foundation of a system that is capable of monitoring copper status and reprioritizing copper usage at both the cellular and systemic levels of organization. While the identification of relevant molecular mechanisms and signaling pathways has proven to be difficult and remains a barrier to our full understanding of the regulation of copper homeostasis, mounting evidence points to the mitochondrion as a pivotal hub in this regard in both healthy and diseased states. Here, we review our current understanding of copper handling pathways contained within the organelle and consider plausible mechanisms that may serve to functionally couple their activity to that of other cellular copper handling machinery to maintain copper homeostasis.

show abstract

“…Until now, there had been no proof that a reductive system works within the IMS. However, two recent publications have identified the putative presence of two known cytosolic reductive pathways in the IMS: the thioredoxin pathway and the glutaredoxin pathway (Vögtle et al 2012; Kojer et al 2015). …”

Section: Disulfide Bond Formation In the Bacterial Periplasm The Er mentioning

confidence: 99%

“…A recent study by the Riemer group showed that the IMS seems to harbour glutaredoxin activity, carried out mainly by Grx2 (Kojer et al 2015). Grx2 is a dually localised protein, which is produced in two forms: a shorter form which is localised in the cytosol, and a more elongated form which is targeted to the mitochondrial matrix (Porras et al 2006, 2010).…”

Section: Disulfide Bond Formation In the Bacterial Periplasm The Er mentioning

confidence: 99%

“…They found that altering the levels of Grx2 in the IMS leads to a shift in the redox state of Mia40, making it present in a primarily reduced state, thus indirectly affecting the import and folding of Mia40-dependent substrates (e.g. Atp23 and Ccs1) (Kojer et al 2015). Interestingly, Grx2 was not identified in the yeast IMS proteome study (Vögtle et al 2012), a fact that can possibly be attributed to the very low levels present in the IMS, as hypothesised by Kojer et al (2015).…”

Section: Disulfide Bond Formation In the Bacterial Periplasm The Er mentioning

confidence: 99%

See 1 more Smart Citation

Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

2016

View full text Add to dashboard Cite

Mitochondria are organelles that play a central role in cellular metabolism, as they are responsible for processes such as iron/sulfur cluster biogenesis, respiration and apoptosis. Here, we describe briefly the various protein import pathways for sorting of mitochondrial proteins into the different subcompartments, with an emphasis on the targeting to the intermembrane space. The discovery of a dedicated redox-controlled pathway in the intermembrane space that links protein import to oxidative protein folding raises important questions on the redox regulation of this process. We discuss the salient features of redox regulation in the intermembrane space and how such mechanisms may be linked to the more general redox homeostasis balance that is crucial not only for normal cell physiology but also for cellular dysfunction.

show abstract

Kinetic control by limiting glutaredoxin amounts enables thiol oxidation in the reducing mitochondrial intermembrane space

Cited by 64 publications

References 51 publications

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

The mitochondrion: a central architect of copper homeostasis

Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

Contact Info

Product

Resources

About