A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology

David J. Pagliarini, Sarah E. Calvo, Betty Chang, Sunil A. Sheth, Scott B. Vafai, Shao En Ong, Geoffrey A. Walford, Canny Sugiana, Avihu Boneh, William K. Chen, David E. Hill, Marc Vidal, James G. Evans, David R. Thorburn, Steven A. Carr, Vamsi K. Mootha

Research output: Contribution to journalArticlepeer-review

1367 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)112-123
Number of pages12
JournalCell
Volume134
Issue number1
DOIs
StatePublished - Jul 11 2008

Keywords

  • CELLBIO
  • HUMDISEASE
  • SYSBIO

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