The human body produces molecules from vitamin B5. This molecule plays a central role in metabolism, the network of chemical reactions that keep cells alive and functioning. If the body is unable to produce this molecule properly, the effects can be far-reaching. Problems with its production can disrupt many organ systems and be associated with several diseases.
Scientists know that most of this molecule, called the essential cofactor Coenzyme A (CoA), resides within mitochondria, structures within cells responsible for producing energy and managing metabolism. In fact, 95% of CoA is concentrated in mitochondria. However, researchers have long been unclear about how CoA actually reaches these mobile power centers.
A new study by researchers at Yale University shows that natural metabolismit became clear that CoA is transported into mitochondria via specific cellular mechanisms. The researchers also identified the transport systems involved in moving molecules into these energy-producing structures.
Understanding this process may ultimately help scientists decide when and where to target diseases associated with CoA dysfunction.
How do mitochondria take up coenzyme A?
Because CoA molecules rarely exist alone in cells, it has been difficult to elucidate how CoA reaches mitochondria. CoA binds to many other molecules as a cofactor. When these combinations are formed, they produce compounds known as CoA conjugates that have different chemical structures.
“That makes it difficult to study this and understand CoA comprehensively,” says lead author Hongyin Shen, Ph.D., associate professor of cellular and molecular physiology at Yale School of Medicine and member of the Systems Biology Institute on Yale’s West Campus.
To overcome this obstacle, Shen’s lab developed a new strategy to analyze all types of CoA complexes within cells. This method relies on mass spectrometry, a technique that allows scientists to detect and measure a variety of molecules with high precision.
Using this approach, the research team identified 33 types of CoA conjugates throughout the cell and 23 types of CoA conjugates specifically within mitochondria.
The next question was whether the CoA complexes found within mitochondria were generated there or transported from elsewhere within the cell.
Further experiments provided important clues. The enzymes required for CoA production are primarily located outside the mitochondria. Furthermore, when the researchers created cells that lacked the molecular transporter responsible for moving CoA, the amount of CoA in the mitochondria was dramatically reduced.
“These findings strongly support the idea that CoA is imported into mitochondria and that these transporters are required for this to occur,” Shen says.
Why is coenzyme A important for disease?
This discovery improves scientists’ understanding of how CoA works and how cells deliver it to where it is needed most. This knowledge also provides insight into how disruption of this process can lead to disease.
For example, mutations in the gene that produces the CoA transporter are thought to be associated with encephalomyopathy, which is associated with developmental delay, epilepsy, and decreased muscle tone. Mutations in enzymes that help produce CoA have also been linked to neurodegenerative diseases.
Shen and colleagues are currently studying how CoA levels within mitochondria are regulated in specific cell types, such as neurons. They also want to know how this regulatory issue contributes to disease.
“In the context of brain diseases, such as neurodegeneration and psychiatric disorders, the idea that dysregulated mitochondrial metabolism is a contributing factor is emerging,” Dr. Shen says. She points out that her interest in micronutrients like vitamin B5 is part of Yale’s long history in metabolic research, dating back more than a century to Dr. Lafayette Mendel, the former Sterling Professor of Physiological Chemistry who discovered vitamin A. In the mid-1910s, the vitamin B complex was developed.
“We want to contribute to this legacy and hope that our deep understanding of cellular metabolism can provide new directions for diagnosing and possibly treating these diseases in the future.”
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 a Klingenstein-Simmons Fellowship.
