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There's a molecule that our body makes from vitamin B₅ that is critical for all of the metabolic processes essential for human life. And when something goes wrong in that molecule's production, it affects nearly every organ system in our body and causes a number of diseases.

Researchers have discovered that up to 95% of this molecule—called essential cofactor coenzyme A (CoA)—is located inside mitochondria, organelles that supply cellular energy and regulate cellular metabolism. But what has not been clear is how CoA gets there.

Reporting in , Yale researchers have now uncovered that CoA is trafficked into mitochondria and have identified the mechanisms responsible.

This information, the researchers say, is important for future considerations about when and where to target treatments for diseases in which CoA is implicated.

Mitochondria import CoA

One reason it has been difficult to pin down how CoA gets to mitochondria is CoA doesn't exist by itself. As a cofactor, it attaches to lots of other molecules, and when bound together, the resulting molecules—called CoA conjugates—have entirely different structures.

"That makes this difficult to study, to have a holistic understanding about CoA," says senior author Hongying Shen, Ph.D., associate professor of cellular and molecular physiology at Yale School of Medicine and a member of the Systems Biology Institute at Yale West Campus.

To address this challenge, Shen's lab developed a new method to profile all of the different CoA conjugates using their expertise in mass spectrometry—a technique that can identify and quantify different molecules.

With this new approach, the researchers were able to identify 33 different CoA conjugates in whole cells as well as 23 CoA conjugates in mitochondria.

The question then was whether the CoA conjugates in the mitochondria were made there or brought in from elsewhere.

In additional experiments, the researchers discovered that the enzyme required to make CoA largely exists outside of mitochondria. Further, when they made cells that lacked the molecular transporters that can move CoA around, mitochondria had far less CoA.

"These findings strongly support the idea that CoA is being imported into mitochondria, and these transporters are required for that to happen," says Shen.

From function to disease

This study advances the fundamental understanding of CoA and how it gets to where it needs to be in order to perform its essential functions. That, in turn, sheds light on how disruptions of this process might contribute to illness.

For instance, mutations in the genes that produce CoA transporters are associated with diseases such as encephalomyopathy, a disorder that can include neurodevelopmental delay, epilepsy, and decreased muscle tone. Mutations in the enzymes that produce CoA have been implicated in neurodegeneration.

Going forward, Shen and her lab are investigating what role mitochondria CoA regulation plays in specialized cell types, such as neurons, and how dysregulation might contribute to disease.

"In the context of brain disorders, such as neurodegeneration and psychiatric disorders, there's an emerging idea that dysregulated mitochondrial metabolism is a contributor," says Shen, who notes that her interest in micronutrients like vitamin B₅ is part of a long Yale history in metabolism stretching back more than a century to Lafayette Mendel, Ph.D., former Sterling Professor of Â鶹ÒùÔºiological Chemistry whose discoveries included vitamin A and vitamin B complex in the mid-1910s.

"We hope to contribute to this legacy and with our deep understanding of cellular metabolism, we hope we can provide new directions for diagnosing and possibly treating these diseases down the road."