Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jan;367(1):43-57.
doi: 10.1007/s00441-016-2488-5. Epub 2016 Sep 8.

Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

Phanee Manganas  1 , Lisa MacPherson  1 , Kostas Tokatlidis  2
Affiliations
Review

Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

Phanee Manganas et al. Cell Tissue Res. 2017 Jan.

Abstract

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.

Keywords: Intermembrane space; Mitochondria; Oxidative folding; Protein import; Redox regulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest or any commercial associations.

Figures

Fig. 1
Fig. 1
Mitochondria are involved in a series of different cellular processes. These include physiological cellular functions, such as respiration and metabolic regulation, essential chemical processes, such as iron/sulfur cluster biogenesis and oxidative folding, as well as signalling mechanisms involving molecules such as calcium and reactive oxygen species. Mitochondria also play an important role during disease and cellular dysfunction and are responsible for the initiation of apoptosis. The figure is a schematic of mitochondrial structure and is not drawn to scale
Fig. 2
Fig. 2
Mitochondrial import pathways. Incoming proteins interact with cytosolic chaperones (Hsp70/Hsp90) and enter the mitochondria through the general entry gate, the translocase of the outer membrane (TOM) complex. a Protein import into the outer membrane of mitochondria. Once the precursors are localised in the intermembrane space (IMS), they interact with the mitochondrial chaperone translocase of the inner membrane (TIM9/10) complex and are targeted to the sorting and assembly machinery (SAM) complex for insertion into the outer membrane. This pathway is followed by β-barrel proteins. The less well-studied mitochondrial import pathway (MIM) may be responsible for the insertion of single- or multi-spanning α-helical outer membrane proteins, in a mechanism that remains unknown. b Protein import into the inner membrane of mitochondria. In the IMS, the precursors interact with the mitochondrial chaperone (TIM22) complex and are inserted into the inner membrane. c Protein import into the matrix. Proteins that are destined to the innermost compartment of mitochondria follow the mitochondrial chaperone (TIM23) pathway. The presence of a positively charged N-terminal MTS guides the protein through the TIM23 complex, with the translocation being facilitated by the presequence translocase-associated motor (PAM) complex. After the protein has been imported into the matrix, the mitochondrial processing peptidase (MPP) cleaves the MTS and the mature protein is released. d Protein import into the mitochondrial intermembrane space. In the IMS, proteins that contain bipartite presequences follow a variation of the TIM23 pathway known as a “stop-transfer”. The precursors are partially translocated into the matrix and become arrested at the TIM23 pore due to the presence of a hydrophobic region. Through the action of the MPP and the inner membrane protease (IMP), the protein is released into the IMS. Proteins that contain cysteine residues interact with the oxidoreductase Mia40, which is responsible for the introduction of disulfide bonds, therefore trapping them in the IMS
Fig. 3
Fig. 3
Cellular redox regulation. Cells have a series of different mechanisms to combat the effects of redox imbalance. These can be divided into two categories: small molecules, such as H2O2 and glutathione, which act like signals and are important for the initiation of the redox response; and proteins, which are able to detect alterations in the levels of reactive oxygen species (Gpx3, Sod1), the GSH:GSSG ratio (glutaredoxin system) as well as in the redox state of proteins (thioredoxin system). The structures shown were obtained from the PDB website (http://www.rcsb.org/pdb/home/home.do) and are the following: thioredoxin pathway—Trx1 (PDB code: 2N5A), glutaredoxin pathway—Grx2 (PDB code: 3CTF), Gpx3 (PDB code: 3CMI) and Sod1 (PDB code: 1SDY)
Fig. 4
Fig. 4
Summary of the components for disulfide bond formation in the bacterial periplasm, the endoplasmic reticulum (ER) and the mitochondrial intermembrane space (IMS). Each of the compartments where oxidative folding occurs is highlighted in dark blue. All three compartments have a similar layout and contain proteins with comparable functions. The main difference is present in the last column. The only compartment with a well-characterised reductive system is the periplasm. The ER has no known reductive pathway. In the IMS, the recent localisation of Grx2 and Trx1/Trr1 gives rise to a series of new questions concerning the characterization of a reductive pathway in this particular compartment
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abe Y, Shodai T, Muto T, et al. Structural basis of presequence recognition by the mitochondrial protein import receptor Tom20. Cell. 2000;100:551–60. doi: 10.1016/S0092-8674(00)80691-1. - DOI - PubMed
    1. Alcock FH, Grossmann JG, Gentle IE, et al. Conserved substrate binding by chaperones in the bacterial periplasm and the mitochondrial intermembrane space. Biochem J. 2008;409:377–87. doi: 10.1042/BJ20070877. - DOI - PubMed
    1. Anelli T, Sitia R. Protein quality control in the early secretory pathway. EMBO J. 2008;27:315–27. doi: 10.1038/sj.emboj.7601974. - DOI - PMC - PubMed
    1. Ang SK, Lu H. Deciphering structural and functional roles of individual disulfide bonds of the mitochondrial sulfhydryl oxidase Erv1p. J Biol Chem. 2009;284:28754–61. doi: 10.1074/jbc.M109.021113. - DOI - PMC - PubMed
    1. Bader M, Muse W, Ballou DP, et al. Oxidative protein folding is driven by the electron transport system. Cell. 1999;98:217–27. doi: 10.1016/S0092-8674(00)81016-8. - DOI - PubMed

LinkOut - more resources