Researchers at the University of Michigan have discovered that the FDA-approved drug Fedratinib may promote communication between two critical cellular organelles—the endoplasmic reticulum and mitochondria—offering new insights into cellular metabolism and potential therapeutic strategies for multiple diseases.
Cells function much like complex cities, with different organelles performing specialized roles. Mitochondria generate energy, the endoplasmic reticulum acts as a transport network, and lysosomes manage waste disposal. For cells to function efficiently, these organelles must communicate through structures known as membrane contact sites.
One of the most abundant of these interactions occurs between the endoplasmic reticulum and mitochondria at structures called ER-mitochondria contact sites (ERMCS). Disruptions in ERMCS organization have been linked to several serious health conditions, including Cancer, Diabetes, Obesity, and Neurodegenerative Diseases. However, scientists have had limited understanding of the mechanisms that regulate these structures.
In the new study, researchers screened a library of FDA-approved drugs using human and mouse cell lines to identify compounds capable of influencing ERMCS formation. They discovered that fedratinib significantly increased the formation of these contact sites. Notably, the effect was reversible once the drug was removed from the cells.
The team determined that fedratinib works by inhibiting the protein BRD4, which regulates how cells read DNA during transcription. This inhibition activates a transcriptional pathway that promotes the formation of ER-mitochondria contact sites.
“Over the past few decades, researchers have seen that cell organelles work in conjunction and they need to talk to each other to do that,” said Yatrik Shah, Professor of Molecular and Integrative Physiology and member of the Rogel Cancer Center at the University of Michigan. “By identifying this signaling pathway, we can better understand how these contact sites are sustained.”
Using advanced electron microscopy, the researchers also identified notable structural changes in ERMCS sites following fedratinib treatment. The analysis revealed that the endoplasmic reticulum formed a three-dimensional envelope around mitochondria in certain cells. Approximately 30% of mitochondria displayed structural alterations, suggesting that mitochondria with extensive contact sites may support specialized metabolic pathways.
Interestingly, similar structural patterns have previously been observed in cells infected with COVID‑19 caused by SARS‑CoV‑2 and in metastatic melanoma cells.
“There were different populations of mitochondria that differed in their degree of contact with the endoplasmic reticulum,” said Drew Stark, a graduate researcher and the study’s first author. “Those with abundant contact sites may be supporting distinct metabolic processes within the cell.”
Researchers are now exploring whether these effects can also be observed in mouse models and how these mitochondrial changes influence metabolism and disease progression. The findings may open new directions for studying metabolic regulation and developing therapies targeting cellular communication pathways.
The research was supported by multiple grants from the National Institutes of Health and collaborating institutions.
