Article

A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell (Impact Factor: 32.24). 08/2008; 134(1):112-23. DOI: 10.1016/j.cell.2008.06.016
Source: PubMed

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.

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Available from: Shao-En Ong, Dec 30, 2013
    • "Synthesis of the mitochondrial respiratory chain complexes requires coordinated gene expression from two genomes and two sets of ribosomes. Approximately99% of the mitochondrial proteome is nuclear encoded (Pagliarini et al., 2008), but a compact mitochondrial genome has been maintained within the organelle of metazoans to ensure transcription and translation of a small number of proteins required for assembly into multisubunit respiratory chain complexes (Christian and Spremulli, 2012; Fox, 2012). The extreme hydrophobicity of these mitochondrially encoded polypeptides and the cotranslational insertion of metal moieties have been hypothesized to account for the retention of a mitochondrial genome (Woodson and Chory, 2008). "
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