A mitochondrial protein compendium elucidates complex I disease biology

By D. Pagliarini, Sarah E. Calvo, Betty Chang, S. Sheth, Scott B Vafai, Shao-En Ong, G. Walford, C. Sugiana, A. Boneh, William Chen and 6 more. Cell, 2008

2,054 citations recorded by the source corpus.

Summary Mitochondria are complex organelles whose dysfunction underlies a broad spectrum of human diseases. Identifying all 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/136c33597c0b4e5c8ca95355cdb0065192a7a82b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Mitochondrial DNA mutations and human disease. (2010, methodology): “understanding of the role of mitochondria in health and disease [209,225,226].”
Insights into Ciliary Genes and Evolution from Multi-Level Phylogenetic Profiling (2017, background): “Construction of a negative set linked to an organelle has been performed previously for mitochondria by selecting genes with GO annotations of other cellular compartments (Pagliarini et al. 2008).”
Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans (2009, methodology): “Proteins were detected via tandem mass spectrometry (MS/MS), and abundance was estimated by standard methods using the normalized number (12, 13, 15) or total peak area (14) of matching MS spectra.”
The human mitochondrial transcriptome (2011, neutral): “However, unlike nuclear tRNAs, we did not observe a Dicer-dependent sRNA species cleaved from the 3 0 stem loop of nuclear tRNAs (Pagliarini et al., 2008) (Figures S5H and S5I).”
Importing Mitochondrial Proteins: Machineries and Mechanisms (2009, background): “Mitochondria contain about 1000 (yeast) to 1500 (human) different proteins (Sickmann et al., 2003; Perocchi et al., 2006; Pagliarini et al., 2008).”
MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations (2020, methodology): “First, in 2008, we constructed the MitoCarta inventory (3) based on a Naı̈ve Bayes integration of the following seven experimental and sequence features: (i) in-depth tandem mass spectrometry (MS/MS) of mitochondria isolated from 14 mouse tissues, (ii) prediction of mitochondrial targeting signals u”