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A mitochondrial protein compendium elucidates complex I disease biology.

Cell | Jul 11, 2008

Mitochondria are complex organelles whose dysfunction underlies a broad spectrum of human diseases. Identifying all of the proteins resident in this organelle and understanding how they integrate into pathways represent major challenges in cell biology. Toward this goal, we performed mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues. We link poorly characterized proteins in this inventory to known mitochondrial pathways by virtue of shared evolutionary history. Using this approach, we predict 19 proteins to be important for the function of complex I (CI) of the electron transport chain. We validate a subset of these predictions using RNAi, including C8orf38, which we further show harbors an inherited mutation in a lethal, infantile CI deficiency. Our results have important implications for understanding CI function and pathogenesis and, more generally, illustrate how our compendium can serve as a foundation for systematic investigations of mitochondria.

Pubmed ID: 18614015 RIS Download

Mesh terms: Animals | Databases, Protein | Electron Transport Complex I | Female | Green Fluorescent Proteins | Humans | Leigh Disease | Male | Mass Spectrometry | Mice | Mice, Inbred C57BL | Microscopy, Fluorescence | Mitochondria | Mitochondrial Proteins | Mutation | Organ Specificity | Proteome

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM077465-04
  • Agency: NIDDK NIH HHS, Id: P30 DK043351
  • Agency: NIDDK NIH HHS, Id: DK43351
  • Agency: Howard Hughes Medical Institute, Id: P30 DK057521
  • Agency: NIDDK NIH HHS, Id: DK57521
  • Agency: NIDDK NIH HHS, Id: GM077465
  • Agency: NIGMS NIH HHS, Id: R01 GM077465
  • Agency: NIGMS NIH HHS, Id:

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ClustalW2

Command line version of multiple sequence alignment program Clustal for DNA or proteins. Alignment is progressive and considers sequence redundancy. No longer being maintained. Please consider using Clustal Omega instead which accepts nucleic acid or protein sequences in multiple sequence formats NBRF/PIR, EMBL/UniProt, Pearson (FASTA), GDE, ALN/ClustalW, GCG/MSF, RSF.

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Hmmer

Tool for searching sequence databases for homologs of protein sequences, and for making protein sequence alignments. It implements methods using probabilistic models called profile hidden Markov models (profile HMMs). Compared to BLAST, FASTA, and other sequence alignment and database search tools based on older scoring methodology, HMMER aims to be significantly more accurate and more able to detect remote homologs because of the strength of its underlying mathematical models. In the past, this strength came at significant computational expense, but in the new HMMER3 project, HMMER is now essentially as fast as BLAST.

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Quantity One 1-D Analysis Software

Software used for Bio-Rad imaging systems to acquire, quantitate, and analyze a variety of data. The software allows automatic configuration of imaging systems with appropriate filters, lasers, LEDs, and other illumination sources. It also contains tools for automated analysis of tests and assays such as 1-D electrophoretic gels, western blots, and colony counts.

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