Identification of myoferlin as a component of mitochondria-associated membranes and discovery of a new function in calcium transfer in PDAC cell lines

Pancreatic cancer is one of the deadliest cancers, with a five-year survival rate being less than 9%. This low survival rate is explained by the late diagnosis and the inefficient treatments. Therefore, developing new therapeutic strategies is needed to improve the survival of patients with pancreatic cancer. In this context, targeting cancer cell metabolism has been proposed as a promising approach, since cancer cells adapt their metabolism to face challenging environmental conditions and to fit their needs for proliferation. Many proteins have been proposed as therapeutic targets, where their targeting enables to create a metabolic imbalance, sensitizing cancer cells to other therapeutics treatments. One of these proteins, named myoferlin, is overexpressed in pancreatic cancer, where it influences cell metabolism. Indeed, myoferlin silencing in pancreatic cancer cells impairs lysosomes integrity, endosomal trafficking and also decreases mitochondrial respiration, which is associated with a fragmented network. Since mitochondria have been reported as key actors for proliferation, relapse and resistance to chemotherapy, we aimed at investigating the role of myoferlin in mitochondrial metabolism and dynamics. We first hypothesized that myoferlin was directly involved in
mitochondrial dynamics and metabolism by being present on this organelle and by interacting with proteins involved in mitochondrial dynamics. Interestingly, we found that myoferlin is interacting with MFNs, proteins involved in mitochondrial fusion. However, our results suggested that myoferlin is unlikely located on mitochondria but is rather located in the membranes associated with this organelle. Due to its peculiar structure and reported function in the cell, we investigated a potential function for myoferlin in calcium transfer between endoplasmic reticulum and mitochondria. Our results showed that myoferlin silencing significantly reduces the mitochondrial calcium level upon stimulation, probably through its interaction with IP3R3. This discovery improves our comprehension of myoferlin function in cancer biology and could be extended to other myoferlin functions in a non-cancer context.