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Import and oxidative folding of proteins in the mitochondrial intermembrane space differ among eukaryotic lineages. While opisthokonts such as yeast rely on the receptor and oxidoreductase Mia40 in combination with the Mia40:cytochrome oxidoreductase Erv, kinetoplastid parasites and other Excavata/Discoba lack Mia40 but have a functional Erv homologue. Whether excavate Erv homologues rely on a Mia40 replacement or directly interact with imported protein substrates remains controversial. Here, we used the CRISPR-Cas9 system to generate a set of tagged and untagged homozygous mutants of from the kinetoplastid model parasite Leishmania tarentolae. Modifications of the shuttle cysteine motif of Erv were lethal, whereas replacement of clamp residue Cys or removal of the kinetoplastida-specific second (KISS) domain had no impact on parasite viability under standard growth conditions. However, removal of the KISS domain rendered parasites sensitive to heat stress and led to the accumulation of homodimeric and mixed Erv disulfides. We therefore determined and compared the redox interactomes of tagged wild-type Erv and Erv using stable isotope labeling by amino acids in cell culture (SILAC) and quantitative mass spectrometry. While the Mia40-replacement candidate Mic20 and all but one typical substrate with twin CxC-motifs were absent in both redox interactomes, we identified a small set of alternative potential interaction partners with putative redox-active cysteine residues. In summary, our study reveals parasite-specific intracellular structure-function relationships and redox interactomes of Erv with implications for current hypotheses on mitochondrial protein import in nonopisthokonts. The discovery of the redox proteins Mia40/CHCHD4 and Erv1/ALR, as well as the elucidation of their relevance for oxidative protein folding in the mitochondrial intermembrane space of yeast and mammals, founded a new research topic in redox biology and mitochondrial protein import. The lack of Mia40/CHCHD4 in protist lineages raises fundamental and controversial questions regarding the conservation and evolution of this essential pathway. Do protist Erv homologues act alone, or do they use the candidate Mic20 or another protein as a Mia40 replacement? Furthermore, we previously showed that Erv homologues in L. tarentolae and the human pathogen L. infantum are not only essential but also differ structurally and mechanistically from yeast and human Erv1/ALR. Here, we analyzed the relevance of such structural differences and determined the first redox interactomes of a nonopisthokont Erv homologue. Our data challenge recent hypotheses on mitochondrial protein import in nonopisthokonts.
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http://dx.doi.org/10.1128/Spectrum.00809-21 | DOI Listing |
Free Radic Biol Med
December 2024
State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences Beijing, Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Institute of Lifeomics, Beijing 102206, China; School of Basic Medicine, Anhui Medical University, Hefei 230032, China; Department of Biomedicine, Medical College, Guizhou University, Guiyang, 550025, China; Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang 110122, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Second Clinical Medicine Collage, Guangzhou Higher Education Mega Center, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Hengyang Medical School, University of South China, Hengyang 421001, China. Electronic address:
Heavy ion radiotherapy is an effective treatment for tumors, but its therapeutic efficacy is limited in cancer cells with radiation resistance. Deinococcus radiodurans, well known for its extremely resisting various stresses, was used to explore radioresistant mechanism. We used quantitative redox proteomics to track the dynamic changes in the global redox state after C irradiation.
View Article and Find Full Text PDFAnim Biosci
December 2024
Department of Integrated Biological Science, Pusan National University, Busan, 46241, Korea.
Objective: Mammalian sperm acquire fertilizing ability in the female reproductive tract and develop hyperactivated motility, which is indispensable for male fertility. Hyperactivated motility is initiated by Ca2+ influx via the sperm-specific ion channel, CatSper. CATSPER1, a CatSper pore subunit, possesses a long N-terminal intracellular domain and its degradation correlates with unsuccessful sperm migration in the female tract.
View Article and Find Full Text PDFFEBS J
December 2024
Redox Metabolism, Institute of Biochemistry, University of Cologne, Germany.
The mitochondrial disulphide relay machinery is essential for the import and oxidative folding of many proteins in the mitochondrial intermembrane space. Its core component, the import receptor MIA40 (also CHCHD4), serves as an oxidoreductase but also as a chaperone holdase, which initially interacts with its substrates non-covalently before introducing disulphide bonds for folding and retaining proteins in the intermembrane space. Interactome studies have identified diverse substrates of MIA40, among them the intrinsically disordered HCLS1-associated protein X-1 (HAX1).
View Article and Find Full Text PDFNIHR Open Res
July 2024
General Intensive Care Unit, University Hospital Southampton, Southamnpton, Hampshire, SO16 6YD, UK.
Background: MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury.
View Article and Find Full Text PDFMol Syst Biol
September 2024
Department of Chemistry, Vanderbilt University, Nashville, TN, 37240, USA.
Many cellular processes are governed by protein-protein interactions that require tight spatial and temporal regulation. Accordingly, it is necessary to understand the dynamics of these interactions to fully comprehend and elucidate cellular processes and pathological disease states. To map de novo protein-protein interactions with time resolution at an organelle-wide scale, we developed a quantitative mass spectrometry method, time-resolved interactome profiling (TRIP).
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