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Poor growth, fatigue and weakness, seizures, developmental and cognitive disabilities, and vision problems are some of the symptoms that can be caused when something goes wrong in the mitochondria. The culprit could be a defect in any of the 1,300 or so proteins that make up mitochondria, but scientists don't know what many of them do.

Researchers at the Washington University School of Medicine in St. Louis and the University of Wisconsin in Madison analyzed dozens of unknown function mitochondria and suggested functions for many of them. They identified the genetic causes of three mitochondrial diseases and proposed another 20 possibilities for further investigation. The findings, published May 25 in Nature, indicate that understanding how the hundreds of proteins in the mitochondria work together to generate power and perform other functions could be a promising path to finding better ways to diagnose and treat such conditions.

We have a parts list for mitochondria, but we don't know what many of the parts do. This study is an attempt to define the functions of as many of those mitochondrial parts as we can so that we can better understand what happens when they don't work.

Mitochondrial diseases affect one in every 4,300 people. People with defects in their mitochondria can have symptoms in any part of the body, although the symptoms tend to be most pronounced in the tissues that need the most energy, such as the heart, brain and muscles.

To better understand how mitochondria work, Pagliarini collaborated with colleagues, including Joshua J. Coon, a professor of biomolecular chemistry and an investigator with the Morgridge Institute for Research.

The researchers used the technology to remove genes from a human cell line. The procedure created a set of related cell lines, each of which had a single gene deleted. There are 50 and 66 missing genes for unknown function and known functions.

They looked at each cell line for clues to the role each missing gene plays in keeping the mitochondria running. The researchers monitored the growth rates of the cells and quantified the levels of 8,433 proteins, 3,563 lipids and 218 metabolites for each cell line. The data they used to build the MITOMICS app was used to equip it with tools to analyze and identify the biological processes that failed when a specific protein went missing.

The researchers proposed possible biological roles for many mitochondrial proteins of unknown function after validation of the approach. They were able to tie three different genes to different conditions.

It is very exciting to see how our mass spectrometry technology platform can generate data on this scale but more importantly, data that can help us understand human disease, Coon said.

A multi systemic disorder is caused by defects in the main energy- producing pathway. A patient with clear signs of the disorder was identified by co-author Robert Taylor, a professor ofMitochondrial Pathology at the University ofNewcastle-upon-Tyne in the United Kingdom. The researchers found a new gene in the pathway and found that the patient had a different version of it.

Pagliarini and colleagues noticed that disrupting one gene, RAB5IF, eliminated a different gene, TMCO1, that was linked to a disease. The condition is characterized by facial features. The researchers collaborated with a professor of human genetics at Hacettepe University in Ankara, Turkey, to show that a variation in RAB5IF was responsible for one case.

Problems with sugar storage were caused by a third gene that was disrupted. Bruno Reversade, PhD, of A*STAR, Singapore's Agency for Science, Technology and Research, published data regarding that syndrome in a paper last year.

We focused on the three conditions, but we found data connecting about 20 other proteins to biological pathways or processes.

The MITOMICS app has been made available to the public to aid scientific discovery. They made it easy for anyone to look for patterns and create plots by clicking around. The data can be downloaded for more advanced analysis.

The hope is that this large dataset becomes one of a number in the field that collectively help us to find better biomarkers and diagnostics for mitochondrial diseases. Our long-term goal is to be able to intervene therapeutically, but we can't do it yet.

More information: David Pagliarini, Defining mitochondrial protein functions through deep multiomic profiling, Nature (2022). DOI: 10.1038/s41586-022-04765-3. Journal information: Nature Citation: Genetic roots of three mitochondrial diseases identified via new approach (2022, May 25) retrieved 25 May 2022 from This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.