Genetic roots of 3 mitochondrial diseases identified by the new approach  University of Washington School of Medicine  Louis

Genetic roots of 3 mitochondrial diseases identified by the new approach University of Washington School of Medicine Louis

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The study provides 20 additional clues, providing a platform for following them

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When something goes wrong in the mitochondria, the tiny organelles that drive cells, it can cause a variety of symptoms, such as poor growth, fatigue and weakness, seizures, developmental and cognitive disorders, and vision problems. A defect in any of the approximately 1,300 proteins that make up the mitochondria could be to blame, but scientists have very little idea what many of these proteins do, making it difficult to identify the defective protein and treat the condition.

Researchers from the Washington University School of Medicine in St. Petersburg. Louis and the University of Wisconsin-Madison systematically analyzed dozens of mitochondrial proteins of unknown function and proposed functions for many of them. Based on these data, they identified the genetic causes of the three mitochondrial diseases as a starting point and suggested another 20 options for further investigation. Findings released on May 25 in Nature suggest that understanding how hundreds of mitochondrial proteins work together to produce energy and perform other organelle functions could be a promising way to find better ways to diagnose and treat such conditions.

“We have a list of parts for mitochondria, but we don’t know what many of these parts do,” said co-author David J. Pagliarini, PhD, Professor Hugo F. and Ina C. Urbauer, and BJC investigator at the University of Washington. “It’s like having a problem with a car, you brought it to a mechanic and said after opening the hood, ‘We’ve never seen half of these parts before.” They wouldn’t know how to fix it. This study is an attempt to define the functions of as many of these mitochondrial parts as possible so that we can better understand what happens when they do not work, and ultimately we have a better chance of devising therapeutics to correct these problems. ”

Mitochondrial diseases are a group of rare genetic conditions that together affect one in every 4,300 people. Because mitochondria provide energy to almost all cells, people with mitochondrial defects can have symptoms in any part of the body, although the symptoms tend to be most pronounced in the tissues that require the most energy, such as the heart, brain, and muscles. .

To better understand how mitochondria work, Pagliarini teamed up with colleagues, including co-author Joshua J. Coon, PhD, professor of biomolecular and UW-Madison chemistry, and researcher at the Morgridge Institute for Research; and co-authors Jarred W. Rensvold, PhD, a former scientist at Pagliarini’s Laboratory, and Evgenia Shishkova, PhD, a researcher at Coon’s Laboratory, to identify the functions of as many mitochondrial proteins as possible.

The researchers used CRISPR-Cas9 technology to remove individual genes from a human cell line. The procedure created a set of related cell lines, each from the same original cell line, but with a single gene deleted. The missing genes encoded 50 mitochondrial proteins of unknown function and 66 mitochondrial proteins of known function.

They then examined each cell line to see what role each missing gene normally played in keeping mitochondria running properly. The researchers monitored the growth rate of the cells and quantified the levels of 8,433 proteins, 3,563 lipids and 218 metabolites for each cell line. They used the data to create the MITOMICS (mitochondrial orphan protein multi-omics CRISPR screen) application and equipped it with tools to analyze and identify biological processes that failed when a particular protein disappeared.

After verifying the mitochondrial protein approach of known function, the researchers proposed possible biological roles for many mitochondrial proteins of unknown function. With further investigation, they were able to bind three proteins to three separate mitochondrial states.

“It’s very exciting to see how our mass spectrometry technology platform can generate data at this scale, but more importantly, data that can directly help us understand human disease,” Coon said.

One condition is a multisystem failure caused by defects in the main energy-producing pathway. Co-author Robert Taylor, PhD, DSc, a professor of mitochondrial pathology at Newcastle University in Newcastle-upon-Tyne, UK, identified a patient with clear signs of the disorder but no mutations in the usual suspected genes. The researchers identified a new gene in the pathway and showed that the patient carried a mutation in it.

Separately, Pagliarini and colleagues noticed that a single gene was disrupted RAB5IFeliminated a protein encoded by another gene, TMCO1which has been associated with cerebrofaciothoracic dysplasia. This condition is characterized by strong facial features and severe mental disabilities. In collaboration with Nurten Akarsu, PhD, a professor of human genetics at Hacettepe University in Ankara, Turkey, researchers have shown that mutations in RAB5IF was responsible for one case of cerebrofaciothoracic dysplasia and two cases of cleft lip in one Turkish family.

The third gene, when disrupted, led to sugar storage problems, which contributed to the fatal auto-inflammatory syndrome. Data on the syndrome were published last year in an article led by Bruno Reversade, PhD, of A * STAR, the Singapore Science, Technology and Research Agency.

“We focused primarily on three conditions, but we found data linking about 20 other proteins to biological pathways or processes,” said Pagliarini, professor of cell biology and physiology, biochemistry and molecular biophysics and genetics. “We can’t get 20 stories in one article, but we created hypotheses and put them there for us and others to test.”

To support the scientific discovery, Pagliarini, Coon and colleagues made the MITOMICS application available to the public. They have built in several user-friendly analytics tools so anyone can search for patterns and create graphs with just a click. All data can be downloaded for more advanced analysis.

“We hope that this large data set will become one of a number in the industry that together will help us design better biomarkers and diagnoses of mitochondrial diseases,” Pagliarini said. “Every time we discover the function of a new protein, it gives us a new opportunity to focus therapeutically on the journey. Our long-term goal is to understand mitochondria in enough depth to be able to intervene therapeutically, which we don’t know yet. ”

Rensvold JW, Shishkova E, Sverchkov Y, Miller IJ, Cetinkaya A, Pyle A, Manicki M, Brademan DR, Alanay Y, Raiman J, Jochem A, Hutchins PD, Peters SR, Linke V, Overmyer KA, Salome AZ, Hebert AS , Vincent CE, Kwiecien NW, Rush MJ, Westphall MS, Craven M, Akarsu NA, Taylor RW, Coon JJ, Pagliarini DJ. Defining the functions of mitochondrial proteins using deep multi-omic profiling. Nature. May 25, 2022. DOI: 10.1038 / s41586-022-04765-3

This work was supported by the National Institutes of Health (NIH), grant numbers R35 GM131795, P41 GM108538 and U54 AI117924; University of Wisconsin, Madison; BJC Investigators Program of the University of Washington School of Medicine; Turkish Scientific and Technological Research Council, ERA-NET Grant No. 108S420 for Rare Diseases Research; CRANIRARE consortium, grant number R07197KS; Wellcome Center for Mitochondrial Research, Grant Number 203105 / Z / 16 / Z; International Center for the Genomic Medicine of Neuromuscular Diseases Medical Research Council, grant number MR / S005021 / 1; award from the UK NIHR Biomedical Research Center for Aging and Age-Related Diseases for the Newcastle upon Tyne Hospitals NHS Trust; cohort of patients with mitochondrial disease in the United Kingdom, grant number G0800674; Lily Foundation; Pathology Society; and the UK’s highly specialized NHS service for rare mitochondrial disorders.

The 1,700 physicians at the Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Petersburg Children’s Hospitals. Louis. The School of Medicine is a leader in medical research, teaching and patient care and is currently No. 4 in research funding from the National Institutes of Health (NIH). Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals is a School of Medicine affiliated with BJC HealthCare.

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