Yale scientists have uncovered how coenzyme A, a vital molecule derived from vitamin B5, enters mitochondria to power life-sustaining metabolism. Credit: Stock

Yale researchers revealed how vitamin B5 fuels mitochondria, offering new insight into brain and metabolic disorders.

The human body produces a molecule from vitamin B5 that plays a crucial role in nearly every metabolic process needed for life. When the production of this molecule is disrupted, it can impact multiple organ systems and lead to various diseases.

Scientists have found that as much as 95% of this molecule, known as the essential cofactor coenzyme A (CoA), is concentrated inside mitochondria, the cellular structures responsible for generating energy and regulating metabolism. However, how CoA enters these organelles has remained a mystery.

In a study published in Nature Metabolism, Yale researchers have now revealed that CoA is actively transported into mitochondria and have identified the specific mechanisms involved.

According to the research team, this discovery offers valuable insight for developing targeted therapies for diseases linked to CoA dysfunction.

Tracking CoA transport into mitochondria

Understanding how CoA reaches mitochondria has been challenging because CoA rarely exists in isolation. As a cofactor, it binds to many different molecules, forming compounds known as CoA conjugates that have distinct 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 research team created a new method to map all forms of CoA conjugates by applying their expertise in mass spectrometry, a technique that allows scientists to detect and measure different molecules with high precision.

Using this strategy, the researchers identified 33 distinct CoA conjugates within whole cells and 23 within mitochondria.

The next step was to determine whether these mitochondrial CoA conjugates were synthesized inside the organelle or transported there from another location.

Through further experiments, the team found that the enzyme responsible for producing CoA is primarily located outside the mitochondria. Moreover, when they engineered cells lacking the molecular transporters that shuttle CoA, the mitochondria contained significantly lower amounts of it.

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

Connecting CoA transport to disease mechanisms

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 encephalopmyopathy, 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 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.”

Reference: “Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism” by Ran Liu, Zihan Zhang, Aye K. Kyaw, Kariona A. Grabińska, Hardik Shah and Hongying Shen, 9 September 2025, Nature Metabolism.
DOI: 10.1038/s42255-025-01358-y

The research reported in this news article was supported by the National Institutes of Health (award R35GM150619) and Yale University. Additional support was provided by the 1907 Foundation, the Rita Allen Foundation, and the Klingenstein-Simons Fellowship.

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