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Three Newly Identified Mitochondrial Proteins May Play Role in Disease

NEW YORK (GenomeWeb) – A team, led by researchers from the University of Wisconsin–Madison mapped a significant part of the mitochondrial proteome and identified three little-known mitochondrial proteins that potentially play a role in disease.

The research is part of a larger project led by Dave Pagliarini, director of metabolism for the Morgridge Institute for Research and UW-Madison associate professor. The goal is to build a complete map of mitochondrial function by identifying more than 200 proteins associated with mitochondria that currently have no defined function in order to gain a greater understanding of mitochondrial disease. Mitochondrial disease strike about one in 4,000 people, and there are currently no approved therapies available.

Pagliarini's lab collaborated with Josh Coon's laboratory at UW–Madison. Coon's lab uses cutting edge spectrometry techniques, which the researchers used to gain clues about the functions of uncharacterized proteins by mapping their interactions with known ones. As the researchers reported in two related studies in Molecular Cell, they performed over 1,000 mass spectrometry experiments.

In the first paper, the researchers characterized the function of mitochondrial proteins with unknown function, or MXPs, by establishing MXP-specific interactions using affinity enrichment mass spectrometry. They prioritized a set of MXPs and supplemented them with 27 mitochondrial proteins of known function and a variant of green fluorescent protein. They then performed an interaction analysis in two cell lines, HEK293 and HepG2, and further analyzed the protein eluate using nanoflow liquid chromatography coupled to high resolution MS.

"We found about 2,000 interactions that we think are particularly robust, out of more than 100,000 total," Pagliarini said in a statement. "These top 2 percent of interactions are really telling us something about protein function and will be very useful to the research community in the years ahead."

In addition to fleshing out the mitochondrial proteome, the researchers also identified a previously unknown protein, C17orf89, which plays a key role in the assembly of complex I — the first of a series of protein complexes used to create adenosine triphosphate (ATP). They found that the absence of this protein was linked to complex I deficiencies which represent the largest class of inborn metabolism error.

"Patients with complex I deficiencies are unable to turn sugar and other sources of fuel into energy," Brendan Floyd, a UW-Madison MD-PhD student and co-author, said in a statement. "They can't make ATP and complete other processes. Symptoms can be very wide-ranging, from severe inborn diseases that are fatal, to effects later in life related to the inability to grow properly or exercise."

Floyd and his colleagues confirmed this finding by examining a patient with complex I disorder who turned out to have a deficiency in the identified protein.

The second paper focused on the identification of a link between a protein used in coenzyme Q synthesis and the development of cerebellar ataxia, a disorder which leads to abnormalities in balance, gait and eye movement. Coenzyme Q is essential to energy production within all cells. Inborn deficiencies in this molecule can lead to brain and muscular disorders, and can also be present in lower quantities in people with cancer, diabetes, heart conditions, Parkinson's disease, and other conditions.

The researchers found this link by tracing the patho-physiology of disease in Coq8a knockout mice. They collected tissue samples taken from the mice and analyzed the isolated peptides using LC-MS/MS on an Orbitrap Elite mass spectrometer.   

Through their analysis, the researchers also identified two other new proteins, COQ8A and COQ8B, involved in the production and use of coenzyme Q.

Identification of protein function is an essential first step in developing new medical treatments. Over the past 20 years, protein function discoveries have been critical for the development of therapies for cystic fibrosis, and cholesterol-lowering statin drugs. "If we know the biochemical functions of proteins throughout this pathway, we might be able to design therapies or drugs that bypass a dysfunctional step in coenzyme Q production," Jonathan Stefely, a Morgridge postdoc and co-author, said in a statement.

These findings only scratch the surface of useful information that might be found in the protein interaction database, which is public and available to the research community, Pagliarini added. "We hope that researchers around the world will use our data to further understand how these mitochondrial protein work, thereby giving us a chance to fix them when they malfunction," he said.