Scientists from the Broad Institute at MIT, as well as Harvard and Howard Hughes Medical Institute, have not only published the most comprehensive online database of mitochondrial genes, but used it to elucidate an inherited disorder called Complex I disease.
From the Broad Institute statement:
The combined approach produced a list of 1098 genes and their expression across 14 different mouse tissues. Roughly a third of these genes in this “MitoCarta” set had not been associated with mitochondria before, and a quarter of the genes had no known function before this study. The catalog — and its hundreds of novel genes — provided the team with a unique opportunity to explore biological pathways at work in mitochondria. “It can take several graduate students’ careers to figure out what a protein does,” said Calvo. “We didn’t want to spend five years on each one, so we took a more global approach.”
To further investigate mitochondrial biology, the team chose to focus on a central piece of machinery in the organelle, involving a large assembly of proteins known as “complex I” or CI. Deficiency in CI is a common mitochondrial disease with a variety of effects, including liver disease and possibly some forms of Parkinson’s disease. A handful of CI proteins had been described, but many cases of complex I deficiency had no genetic mutations in those proteins, suggesting others remained undiscovered.
One clever way to identify genes with a given function is to examine their evolutionary history. Genes that are involved in similar pathways are typically gained and lost together. As an evolving species loses the need for complex I, it also discards the genes that encode those proteins. By comparing the genomes of 42 species, from yeast to mammals, the researchers homed in on 19 candidate genes suspected to play a role in complex I.
After disabling four of those genes in human cells, the team found one — C8orf38 — especially interesting. In addition to reducing CI activity when disabled, the gene was found to be mutated in two CI-deficient infant siblings, providing evidence that it is a human CI disease gene.
Prior to this study, researchers had no knowledge of what C8orf38’s function was in the cell. In light of the findings in cells and in patients, the new knowledge on C8orf38 and its role in CI biology is a powerful validation of the research team’s approach, said David Pagliarini, a postdoctoral fellow at Massachusetts General Hospital and co-first author of the study.
The new catalog of mitochondrial proteins may prove useful for scientists searching for other genes associated with mitochondrial disorders, like C8orf38 or perhaps others that underlie more common diseases.
Abstract: A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology Cell, Vol 134, 112-123, 11 July 2008
Broad press release: Parts list for a powerhouse…; HHMI press release: The Mighty MitoCarta-Online Mitochondrial Atlas Leads to Cause of Inherited Disease…
Image credit: Wellcome images: Mitochondria in the cell cytoplasm…