A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology
Open accessAbstract
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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In pulsed SILAC data at 24h post LPS and mock stimulation, the M/L ratios decreased for ~80% of annotated mitochondrial proteins in LPS vs MOCK samples, and for nearly all mitochondrial proteins with a higher mitochondrial localization prediction score (over 95% of the 156 proteins with a score >20 of the 472 measured mitochondrial proteins).
“we saw a decrease in the M/L ratios (a proxy for increased degradation) of ~80% of annotated mitochondrial proteins in LPS vs. MOCK samples (Fig. 4D)”
From Dynamic profiling of the protein life cycle in response to pathogens (2015) · cites this paper as [43]
MitoCarta consists of 1098 identified proteins.
“The most recent mammalian mitochondrial compendium (MitoCarta) consists of 1098 identified proteins [209].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [209]
The number of oxidatively-modified mitochondrial proteins characterized may represent a small fraction of the estimated 1100-1400 total mitochondrial proteins.
“The number of oxidatively-modified mitochondrial proteins we characterized may represent a small fraction of the estimated number of 1100–1400 total mitochondrial proteins [40], [41].”
A recent compendium of mitochondrial proteins from 14 different mouse tissues indicates that white adipocyte mitochondria contain a more diverse protein repertoire than mitochondria from heart, skeletal muscle, or brain.
“Interestingly, a recent compendium of mitochondrial proteins from 14 different mouse tissues indicates that white adipocyte mitochondria contain a more diverse protein repertoire than mitochondria from heart, skeletal muscle, or brain (31).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [31]
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- Authors
- Pagliarini, D. J., Calvo, S. E., Chang, B., Sheth, S. A., Vafai, S. B., Ong, S.-E., Walford, G. A., Sugiana, C., Boneh, A., Chen, W. K., Hill, D. E., Vidal, M., Evans, J. G., Thorburn, D. R., Carr, S. A., & Mootha, V. K.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- The University of Melbourne (AU)
- Royal Children's Hospital (AU)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Carr, Steven A.
- Mootha, Vamsi K.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 134
- Issue
- 1
- Pages
- 112-123
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2778844
- OpenAlex
- W2101117598
- Cited by
- 1,994
- References
- 50
- Citations by year
- 2026: 54 · 2025: 71 · 2024: 96 · 2023: 81 · 2022: 91 · 2021: 138 · 2020: 117 · 2019: 100 · 2018: 112 · 2017: 104 · 2016: 134 · 2015: 135 · 2014: 147 · 2013: 138 · 2012: 147
- FWCI
- 44.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Boston Area Diabetes Endocrinology Research Center
- Institut National de la Santé et de la Recherche Médicale
- National Institutes of Health
- National Health and Medical Research Council
- National Medical Research Council
- National Institute of General Medical Sciences (GM077465, R01GM077465)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, DK57521, DK 43351, P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial proteome, complex I, electron transport chain, mitochondrial disease, inherited mutations, mouse tissues, protein expression, evolutionary history, mitochondrial pathway
- MeSH terms
- Animals, Female, Humans, Leigh Disease, Male, Mice, Inbred C57BL, Microscopy, Fluorescence, Mitochondria, Mutation, Organ Specificity, Mass Spectrometry, Proteome, Mitochondrial Proteins, Databases, Protein, Electron Transport Complex I, Green Fluorescent Proteins, Mice
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