Mia40 Is Optimized for Function in Mitochondrial Oxidative Protein Folding and Import

Koch, Johanna R.; Schmid, Franz X.

doi:10.1021/cb500408n

Cited by 19 publications

(19 citation statements)

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“…A somewhat different scenario has recently been suggested proposing that Mia40 itself is involved in directing the native folding pathway and in the reshuffling of non-native disulfides acting concurrently as a disulfide isomerase. 34 , 35 However, an isomerase function for Mia40 (or indeed any other protein of the IMS) in vivo is still unclear. Although the twin CX 3 C and CX 9 C substrates, used in all of the reconstitution studies to date, only require two disulfide bonds, other Mia40 substrates require many more.…”

Section: Protein Foldingmentioning

confidence: 99%

The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

Mordas

Tokatlidis

2015

Acc. Chem. Res.

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ConspectusMitochondria are fundamental intracellular organelles with key roles in important cellular processes like energy production, Fe/S cluster biogenesis, and homeostasis of lipids and inorganic ions. Mitochondrial dysfunction is consequently linked to many human pathologies (cancer, diabetes, neurodegeneration, stroke) and apoptosis. Mitochondrial biogenesis relies on protein import as most mitochondrial proteins (about 10–15% of the human proteome) are imported after their synthesis in the cytosol. Over the last several years many mitochondrial translocation pathways have been discovered. Among them, the import pathway that targets proteins to the intermembrane space (IMS) stands out as it is the only one that couples import to folding and oxidation and results in the covalent modification of the incoming precursor that adopt internal disulfide bonds in the process (the MIA pathway). The discovery of this pathway represented a significant paradigm shift as it challenged the prevailing dogma that the endoplasmic reticulum is the only compartment of eukaryotic cells where oxidative folding can occur.The concept of the oxidative folding pathway was first proposed on the basis of folding and import data for the small Tim proteins that have conserved cysteine motifs and must adopt intramolecular disulfides after import so that they are retained in the organelle. The introduction of disulfides in the IMS is catalyzed by Mia40 that functions as a chaperone inducing their folding. The sulfhydryl oxidase Erv1 generates the disulfide pairs de novo using either molecular oxygen or, cytochrome c and other proteins as terminal electron acceptors that eventually link this folding process to respiration. The solution NMR structure of Mia40 (and supporting biochemical experiments) showed that Mia40 is a novel type of disulfide donor whose recognition capacity for its substrates relies on a hydrophobic binding cleft found adjacent to a thiol active CPC motif. Targeting of the substrates to this pathway is guided by a novel type of IMS targeting signal called ITS or MISS. This consists of only 9 amino acids, found upstream or downstream of a unique Cys that is primed for docking to Mia40 when the substrate is accommodated in the Mia40 binding cleft. Different routes exist to complete the folding of the substrates and their final maturation in the IMS. Identification of new Mia40 substrates (some even without the requirement of their cysteines) reveals an expanded chaperone-like activity of this protein in the IMS. New evidence on the targeting of redox active proteins like thioredoxin, glutaredoxin, and peroxiredoxin into the IMS suggests the presence of redox-dependent regulatory mechanisms of the protein folding and import process in mitochondria. Maintenance of redox balance in mitochondria is crucial for normal cell physiology and depends on the cross-talk between the various redox signaling processes and the mitochondrial oxidative folding pathway.

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Section: Protein Foldingmentioning

confidence: 99%

The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

Mordas

Tokatlidis

2015

Acc. Chem. Res.

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“…The interplay with GSH also raised the question whether Mia40/CHCHD4 can serve as disulfide isomerase as many other oxidoreductases. In vitro results support such a function albeit at very low activity (Bien et al ., ; Koch and Schmid, ; Hudson and Thorpe, ).…”

Section: Formation Of Structural Disulfide Bonds In the Imsmentioning

confidence: 98%

“…In yeast, substrates do not rely on typical TOM receptor subunits such as Tom22 for recognition by the TOM complex (Gornicka et al ., ). To interact with substrates, CHCHD4 is equipped with two functional parts, a redox‐active cysteine‐proline‐cysteine (CPC) motif in a flexible N‐terminal region and a hydrophobic patch in a central inflexible core domain (Banci et al ., ; Banci et al ., ; Weckbecker et al ., ; Koch and Schmid, ; Koch and Schmid, ; Peleh et al ., ). During its covalent (formation of a mixed disulfide bond between CHCHD4 and substrate) and non‐covalent (interaction of hydrophobic patches in substrate and CHCHD4) interactions with its substrates, CHCHD4 guides substrates into the IMS, oxidizes and folds them and possibly even helps to assemble them into larger complexes if required.…”

Section: Formation Of Structural Disulfide Bonds In the Imsmentioning

confidence: 99%

Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Habich

Salscheider

Riemer

2018

British J Pharmacology

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The intermembrane space (IMS) is a very small mitochondrial sub-compartment with critical relevance for many cellular processes. IMS proteins fulfil important functions in transport of proteins, lipids, metabolites and metal ions, in signalling, in metabolism and in defining the mitochondrial ultrastructure. Our understanding of the IMS proteome has become increasingly refined although we still lack information on the identity and function of many of its proteins. One characteristic of many IMS proteins are conserved cysteines. Different post-translational modifications of these cysteine residues can have critical roles in protein function, localization and/or stability. The close localization to different ROS-producing enzyme systems, a dedicated machinery for oxidative protein folding, and a unique equipment with antioxidative systems, render the careful balancing of the redox and modification states of the cysteine residues, a major challenge in the IMS. In this review, we discuss different functions of human IMS proteins, the involvement of cysteine residues in these functions, the consequences of cysteine modifications and the consequences of cysteine mutations or defects in the machinery for disulfide bond formation in terms of human health.

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“…Recent work by Koch and Schmid [81], [82], [83] has investigated the kinetics of the interaction between Mia40 and its substrates in vitro . These studies provided further support for the previous findings that characterized the Mia40 system using structural approaches for the analysis of the interactions in organello and in cells.…”

Section: The Mia Pathwaymentioning

confidence: 99%

Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease

Chatzi

Manganas

Tokatlidis

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Mitochondria are fundamental organelles with a complex internal architecture that fulfill important diverse functions including iron–sulfur cluster assembly and cell respiration. Intense work for more than 30 years has identified the key protein import components and the pathways involved in protein targeting and assembly. More recently, oxidative folding has been discovered as one important mechanism for mitochondrial proteostasis whilst several human disorders have been linked to this pathway. We describe the molecular components of this pathway in view of their putative redox regulation and we summarize available evidence on the connections of these pathways to human disorders.

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Mia40 Is Optimized for Function in Mitochondrial Oxidative Protein Folding and Import

Cited by 19 publications

References 50 publications

The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

The MIA Pathway: A Key Regulator of Mitochondrial Oxidative Protein Folding and Biogenesis

Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Oxidative folding in the mitochondrial intermembrane space: A regulated process important for cell physiology and disease

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