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A small molecule inhibitor of redox-regulated protein translocation into mitochondria.

Developmental cell | Apr 15, 2013

http://www.ncbi.nlm.nih.gov/pubmed/23597483

The mitochondrial disulfide relay system of Mia40 and Erv1/ALR facilitates import of the small translocase of the inner membrane (Tim) proteins and cysteine-rich proteins. A chemical screen identified small molecules that inhibit Erv1 oxidase activity, thereby facilitating dissection of the disulfide relay system in yeast and vertebrate mitochondria. One molecule, mitochondrial protein import blockers from the Carla Koehler laboratory (MitoBloCK-6), attenuated the import of Erv1 substrates into yeast mitochondria and inhibited oxidation of Tim13 and Cmc1 in in vitro reconstitution assays. In addition, MitoBloCK-6 revealed an unexpected role for Erv1 in the carrier import pathway, namely transferring substrates from the translocase of the outer membrane complex onto the small Tim complexes. Cardiac development was impaired in MitoBloCK-6-exposed zebrafish embryos. Finally, MitoBloCK-6 induced apoptosis via cytochrome c release in human embryonic stem cells (hESCs) but not in differentiated cells, suggesting an important role for ALR in hESC homeostasis.

Pubmed ID: 23597483 RIS Download

Mesh terms: Animals | Apoptosis | Cell Differentiation | Cell Respiration | Cell Survival | Cytochrome Reductases | Cytochromes c | Edema, Cardiac | Embryo, Nonmammalian | Enzyme Inhibitors | Gene Expression Regulation, Developmental | HEK293 Cells | HeLa Cells | Humans | Microbial Sensitivity Tests | Mitochondria | Mitochondrial Membrane Transport Proteins | Mitochondrial Proteins | Morpholinos | Oxidation-Reduction | Oxygen | Protein Transport | Substrate Specificity | Yeasts | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: 1F32GM084568
  • Agency: NCI NIH HHS, Id: CA156674
  • Agency: NCI NIH HHS, Id: CA90571
  • Agency: NIGMS NIH HHS, Id: GM07185
  • Agency: NIGMS NIH HHS, Id: GM073981
  • Agency: NIGMS NIH HHS, Id: GM08496
  • Agency: NIGMS NIH HHS, Id: GM61721
  • Agency: NIMH NIH HHS, Id: MH085683
  • Agency: NIGMS NIH HHS, Id: P01GM081621
  • Agency: PHS HHS, Id: PNEY018228
  • Agency: NCI NIH HHS, Id: R01 CA090571
  • Agency: NCI NIH HHS, Id: R01 CA156674
  • Agency: NIGMS NIH HHS, Id: R01 GM061721
  • Agency: NIGMS NIH HHS, Id: R01 GM073981
  • Agency: NIMH NIH HHS, Id: R03 MH085683
  • Agency: NCRR NIH HHS, Id: S10RR025631

ZFIN (Data, Gene Expression)

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