Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease

MacPherson, Lisa; Tokatlidis, Kostas

doi:10.1042/bcj20160627

Cited by 11 publications

(10 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They contain more than 1,500 proteins of which only a small number is synthesized in the organelle (Rhee et al , ; Hung et al , ; Calvo et al , ; Morgenstern et al , ). The remainder is translated on cytosolic ribosomes and relies on different mitochondrial import pathways to reach the mitochondrial subcompartments, namely the mitochondrial outer (OMM) and inner (IMM) membranes, the intermembrane space (IMS) and the mitochondrial matrix (Topf et al , ; MacPherson & Tokatlidis, ; Jackson et al , ; Habich et al , 2019b; Hansen & Herrmann, ; Pfanner et al , ).…”

Section: Introductionmentioning

confidence: 99%

Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

et al. 2020

View full text Add to dashboard Cite

Plasticity of the proteome is critical to adapt to varying conditions. Control of mitochondrial protein import contributes to this plasticity. Here, we identified a pathway that regulates mitochondrial protein import by regulated N-terminal processing. We demonstrate that dipeptidyl peptidases 8/9 (DPP8/9) mediate the N-terminal processing of adenylate kinase 2 (AK2) en route to mitochondria. We show that AK2 is a substrate of the mitochondrial disulfide relay, thus lacking an N-terminal mitochondrial targeting sequence and undergoing comparatively slow import. DPP9-mediated processing of AK2 induces its rapid proteasomal degradation and prevents cytosolic accumulation of enzymatically active AK2. Besides AK2, we identify more than 100 mitochondrial proteins with putative DPP8/9 recognition sites and demonstrate that DPP8/9 influence the cellular levels of a number of these proteins. Collectively, we provide in this study a conceptual framework on how regulated cytosolic processing controls levels of mitochondrial proteins as well as their dual localization to mitochondria and other compartments.

show abstract

Section: Introductionmentioning

confidence: 99%

Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The vast majority of mitochondrial proteins are synthesized at cytosolic ribosomes and have to be imported into one of the four mitochondrial compartments [1] . One of these compartments, the intermembrane space (IMS) between the inner and outer mitochondrial membrane, harbors proteins that contribute to respiration, programmed cell death, the assembly of protein complexes, and the transfer of ions, metabolites and proteins [2] , [3] , [4] , [5] , [6] . In addition to a functional classification, IMS proteins can be also grouped according to their protein import pathway (reviewed in [2] , [7] ): One group of proteins, hereinafter referred to as class I proteins, contains a positively charged N-terminal matrix-targeting signal that is followed by a hydrophobic transmembrane segment.…”

Section: Introductionmentioning

confidence: 99%

A single-cysteine mutant and chimeras of essential Leishmania Erv can complement the loss of Erv1 but not of Mia40 in yeast

et al. 2018

View full text Add to dashboard Cite

Mia40/CHCHD4 and Erv1/ALR are essential for oxidative protein folding in the mitochondrial intermembrane space of yeast and mammals. In contrast, many protists, including important apicomplexan and kinetoplastid parasites, lack Mia40. Furthermore, the Erv homolog of the model parasite Leishmania tarentolae (LtErv) was shown to be incompatible with Saccharomyces cerevisiae Mia40 (ScMia40). Here we addressed structure-function relationships of ScErv1 and LtErv as well as their compatibility with the oxidative protein folding system in yeast using chimeric, truncated, and mutant Erv constructs. Chimeras between the N-terminal arm of ScErv1 and a variety of truncated LtErv constructs were able to rescue yeast cells that lack ScErv1. Yeast cells were also viable when only a single cysteine residue was replaced in LtErvC17S. Thus, the presence and position of the C-terminal arm and the kinetoplastida-specific second (KISS) domain of LtErv did not interfere with its functionality in the yeast system, whereas a relatively conserved cysteine residue before the flavodomain rendered LtErv incompatible with ScMia40. The question whether parasite Erv homologs might also exert the function of Mia40 was addressed in another set of complementation assays. However, neither the KISS domain nor other truncated or mutant LtErv constructs were able to rescue yeast cells that lack ScMia40. The general relevance of Erv and its candidate substrate small Tim1 was analyzed for the related parasite L. infantum. Repeated unsuccessful knockout attempts suggest that both genes are essential in this human pathogen and underline the potential of mitochondrial protein import pathways for future intervention strategies.

show abstract

“…Proteolytic processing of mGPDH associated with its import into intermembrane space (IMS) is therefore a much more relevant reason for the observed MW shift. In general, protein targeting into IMS can be achieved via two processes (reviewed in [41,50]). Proteins lacking specific presequence typically follow redox-dependent mitochondrial IMS assembly pathway (Mia/Erv40) and contain twin CX9C or CX3C motifs to form intramolecular disulfide bridges.…”

Section: Discussionmentioning

confidence: 99%

Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer

Pecinová

Alán

Brázdová

et al. 2020

Cells

View full text Add to dashboard Cite

Prostate cancer is one of the most prominent cancers diagnosed in males. Contrasting with other cancer types, glucose utilization is not increased in prostate carcinoma cells as they employ different metabolic adaptations involving mitochondria as a source of energy and intermediates required for rapid cell growth. In this regard, prostate cancer cells were associated with higher activity of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), the key rate limiting component of the glycerophosphate shuttle, which connects mitochondrial and cytosolic processes and plays significant role in cellular bioenergetics. Our research focused on the role of mGPDH biogenesis and regulation in prostate cancer compared to healthy cells. We show that the 42 amino acid presequence is cleaved from N-terminus during mGPDH biogenesis. Only the processed form is part of the mGPDH dimer that is the prominent functional enzyme entity. We demonstrate that mGPDH overexpression enhances the wound healing ability in prostate cancer cells. As mGPDH is at the crossroad of glycolysis, lipogenesis and oxidative metabolism, regulation of its activity by intramitochondrial processing might represent rapid means of cellular metabolic adaptations.

show abstract

Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease

Cited by 11 publications

References 108 publications

Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

Proteasomal degradation induced by DPP9‐mediated processing competes with mitochondrial protein import

A single-cysteine mutant and chimeras of essential Leishmania Erv can complement the loss of Erv1 but not of Mia40 in yeast

Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer

Contact Info

Product

Resources

About