Researchers at the University of Michigan reported on Mar. 13 that the FDA-approved drug fedratinib can promote the formation of contact sites between cell organelles, specifically between the endoplasmic reticulum and mitochondria. The study used human and mouse cell lines to screen a library of FDA-approved drugs for their ability to influence these membrane contact sites.
Communication between different parts of a cell is important for metabolism, and disruptions in these interactions have been linked to diseases such as neurodegeneration, obesity, cancer, and diabetes. Understanding how these contact sites are organized could provide new therapeutic approaches.
The research team found that fedratinib, an anti-cancer drug, increases the formation of endoplasmic reticulum-mitochondria contact sites (ERMCS). This effect was reversible when the drug was removed from the cells. Further investigation revealed that fedratinib inhibits BRD4, a protein involved in controlling gene transcription. This inhibition activates a pathway that leads to increased ERMCS formation.
"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. "By identifying this signaling pathway, we can better understand how these contact sites are sustained."
Electron microscopy showed structural changes at ERMCS sites after treatment with fedratinib. These changes resembled those observed in cells infected with SARS-CoV-2 or in metastatic melanoma cells. "We found 3D envelopment of the endoplasmic reticulum that formed around the mitochondria in our cell lines," said Drew Stark, a graduate student in the Shah and Lyssiotis labs and first author of the paper. "There were also different populations of mitochondria that differed in their degree of contact with the endoplasmic reticulum." About 30% of mitochondria showed structural alterations; researchers believe those with more abundant contacts may support specific metabolic pathways.
The team is now investigating whether similar effects occur in mouse models and aims to determine how these mitochondrial changes affect metabolism or play roles in other diseases.
