Genetic roots of 3 mitochondrial diseases ID’d via new approach: Study yields 20 other clues, provides platform to pursue them

When something goes wrong in mitochondria, the tiny organelles that power cells, it can cause a bewildering variety of symptoms such as poor growth, fatigue and weakness, seizures, developmental and cognitive disabilities, and vision problems. The culprit could be a defect in any of the 1,300 or so proteins that make up mitochondria, but scientists have very little idea what many of those proteins do, making it difficult to identify the faulty protein and treat the condition.

Researchers at Washington University School of Medicine in St. Louis and the University of Wisconsin-Madison systematically analyzed dozens of mitochondrial proteins of unknown function and suggested functions for many of them. Using these data as a starting point, 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 mitochondria’s hundreds of proteins work together to generate power and perform the organelles’ 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,” said co-senior author David J. Pagliarini, PhD, the Hugo F. and Ina C. Urbauer Professor and a BJC Investigator at Washington University. “It’s similar to if you had a problem with your car, and you brought it to a mechanic, and upon opening the hood they said, ‘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 those mitochondrial parts as we can so we have a better understanding of what happens when they don’t work and, ultimately, a better chance at devising therapeutics to rectify those problems.”

Mitochondrial diseases are a group of rare genetic conditions that collectively affect one in every 4,300 people. Since mitochondria provide energy for almost all cells, 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 require the most energy, such as the heart, brain and muscles.

To better understand how mitochondria work, Pagliarini teamed up with colleagues, including co-senior author Joshua J. Coon, PhD, a UW-Madison professor of biomolecular chemistry & chemistry and an investigator with the Morgridge Institute for Research; and co-first authors Jarred W. Rensvold, PhD, a former staff scientist in Pagliarini’s lab, and Evgenia Shishkova, PhD, a staff scientist in Coon’s lab, 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 derived from the same original cell line but with a single gene deleted. The missing genes coded for 50 mitochondrial proteins of unknown function and 66 mitochondrial proteins with known functions.

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