Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

Manganas, Phanee; MacPherson, Lisa; Tokatlidis, Kostas

doi:10.1007/s00441-016-2488-5

Cited by 14 publications

(16 citation statements)

References 140 publications

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“…Like most mitochondrial proteins the small Tims are imported. Their import, similar to that of other small cysteine-rich IMS proteins, is coupled to oxidation of their cysteine residues [ 25 ]. Small Tim proteins are first translocated across the OM through the TOM complex.…”

Section: Introductionmentioning

confidence: 99%

A trypanosomal orthologue of an intermembrane space chaperone has a non-canonical function in biogenesis of the single mitochondrial inner membrane protein translocase

et al. 2017

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Mitochondrial protein import is essential for Trypanosoma brucei across its life cycle and mediated by membrane-embedded heterooligomeric protein complexes, which mainly consist of trypanosomatid-specific subunits. However, trypanosomes contain orthologues of small Tim chaperones that escort hydrophobic proteins across the intermembrane space. Here we have experimentally analyzed three novel trypanosomal small Tim proteins, one of which contains only an incomplete Cx3C motif. RNAi-mediated ablation of TbERV1 shows that their import, as in other organisms, depends on the MIA pathway. Submitochondrial fractionation combined with immunoprecipitation and BN-PAGE reveals two pools of small Tim proteins: a soluble fraction forming 70 kDa complexes, consistent with hexamers and a second fraction that is tightly associated with the single trypanosomal TIM complex. RNAi-mediated ablation of the three proteins leads to a growth arrest and inhibits the formation of the TIM complex. In line with these findings, the changes in the mitochondrial proteome induced by ablation of one small Tim phenocopy the effects observed after ablation of TbTim17. Thus, the trypanosomal small Tims play an unexpected and essential role in the biogenesis of the single TIM complex, which for one of them is not linked to import of TbTim17.

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Section: Introductionmentioning

confidence: 99%

A trypanosomal orthologue of an intermembrane space chaperone has a non-canonical function in biogenesis of the single mitochondrial inner membrane protein translocase

et al. 2017

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“…Following this, the substrate is released from Mia40 in an oxidised, stably folded conformation, thereby remaining trapped in the IMS. The CPC motif of Mia40 is left in a reduced state and requires re-oxidation to restore its capacity to import substrate proteins [ 21 , 25 , 31 ].…”

Section: The Mia Pathway—basic Players and Mechanismmentioning

confidence: 99%

“…The first pair (C30/33) is the shuttle disulphide, which is located at the N-terminus and interacts with Mia40, whilst the third (C159/176) is the structural disulphide that is recognised by Mia40 during Erv1 import. This N-terminal shuttle domain of Erv1 is sufficient and necessary for the non-covalent interaction of Mia40 and Erv1 [ 31 , 35 , 36 , 37 , 38 , 39 ].…”

Section: The Mia Pathway—basic Players and Mechanismmentioning

confidence: 99%

The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space

et al. 2021

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Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron–sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.

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“…A dedicated machinery, the mitochondrial disulfide relay, catalyzes IMS disulfide bond formation. This relay consists of the oxidoreductase CHCHD4 (in yeast: Mia40) and the sulfhydryl oxidase augmenter of liver regeneration ALR (also GFER, hsErv1, in yeast: Erv1) [4] , [5] , [12] , [13] . CHCHD4 contains a redox-active cysteine pair (CPC, where C represents cysteine and P proline), which in its oxidized state can introduce disulfide bonds into substrate proteins.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo

et al. 2018

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Disulfide formation in the mitochondrial intermembrane space is an essential process catalyzed by a disulfide relay machinery. In mammalian cells, the key enzyme in this machinery is the oxidoreductase CHCHD4/Mia40. Here, we determined the in vivo CHCHD4 redox state, which is the major determinant of its cellular activity. We found that under basal conditions, endogenous CHCHD4 redox state in cultured cells and mouse tissues was predominantly oxidized, however, degrees of oxidation in different tissues varied from 70% to 90% oxidized. To test whether differences in the ratio between CHCHD4 and ALR might explain tissue-specific differences in the CHCHD4 redox state, we determined the molar ratio of both proteins in different mouse tissues. Surprisingly, ALR is superstoichiometric over CHCHD4 in most tissues. However, the levels of CHCHD4 and the ratio of ALR over CHCHD4 appear to correlate only weakly with the redox state, and although ALR is present in superstoichiometric amounts, it does not lead to fully oxidized CHCHD4.

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Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

Cited by 14 publications

References 140 publications

A trypanosomal orthologue of an intermembrane space chaperone has a non-canonical function in biogenesis of the single mitochondrial inner membrane protein translocase

A trypanosomal orthologue of an intermembrane space chaperone has a non-canonical function in biogenesis of the single mitochondrial inner membrane protein translocase

The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space

The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo

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