Scientists solve the mystery of a vitamin B5 molecule that powers your cells

Scientists have known that most of this molecule, called essential cofactor coenzyme A (CoA), is found inside mitochondria, the structures in cells responsible for generating energy and managing metabolism. In fact, as much as 95% of CoA is concentrated in mitochondria. However, researchers have long been unsure how CoA actually reaches these cellular power centers.

A new study from Yale researchers, published in Nature Metabolism, reveals that CoA is transported into mitochondria through specific cellular mechanisms. The team also identified the transport systems responsible for moving the molecule into these energy producing structures.

Understanding this process could eventually help scientists determine when and where treatments should target diseases linked to CoA dysfunction.

How Mitochondria Import Coenzyme A

Determining how CoA reaches mitochondria has been challenging because the molecule rarely exists alone inside cells. As a cofactor, CoA attaches to many other molecules. When these combinations form, they create compounds known as CoA conjugates, which have different chemical structures.

"That makes this difficult to study, to have a holistic understanding about CoA," says senior author Hongying Shen, PhD, 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 overcome this obstacle, Shen's laboratory developed a new strategy to analyze the full range of CoA conjugates in cells. The method relies on mass spectrometry, a technology that allows scientists to detect and measure different molecules with high precision.

Using this approach, the team identified 33 types of CoA conjugates across whole cells and 23 types specifically within mitochondria.

The next question was whether the CoA conjugates found inside mitochondria were produced there or transported in from elsewhere in the cell.

Further experiments provided an important clue. The enzyme needed to produce CoA is located mainly outside mitochondria. In addition, when researchers created cells lacking the molecular transporters responsible for moving CoA, the amount of CoA inside mitochondria dropped dramatically.

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

Why Coenzyme A Matters for Disease

The findings improve scientists' understanding of how CoA functions and how cells deliver it to the places where it is needed most. This knowledge also provides insight into how disruptions in this process might lead to disease.

For example, mutations in genes that produce CoA transporters have been linked to encephalopmyopathy, a condition that may involve developmental delays, epilepsy, and reduced muscle tone. Mutations in enzymes that help produce CoA have also been associated with neurodegenerative diseases.

Shen and her colleagues are now studying how CoA levels inside mitochondria are regulated in specific cell types such as neurons. They also want to learn how problems with this regulation 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 the study of metabolism stretching back more than a century to Lafayette Mendel, PhD, former Sterling Professor of Physiological 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."

The research reported in this news article was supported by the National Institutes of Health (award R35GM150619) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the 1907 Foundation, the Rita Allen Foundation, and the Klingenstein-Simons Fellowship.