Researchers have discovered that the FNIP1 protein plays a crucial role in a cell’s ability to sense low energy levels and their efforts to eliminate and replace damaged mitochondria. This discovery uncovers how these signals to make new mitochondria are tied to the original sign that energy levels are low. In a study published in Science, Professor Reuben Shaw and his team have cracked the case behind this process of removing and replacing damaged mitochondria.
Shaw’s lab first discovered that an enzyme called AMPK was responsible for starting the process of removing damaged mitochondria. Later, the team showed that a part of this process involves breaking damaged mitochondria into hundreds of fragments, then sorting through them to remove damaged parts and repurpose functional ones.
But the question remained: how is repairing damaged powerhouses connected to the signal to start making new powerhouses from scratch?
FNIP1 is the most recently discovered protein of the AMPK, TFEB, and FNIP1 trio. The team found that AMPK signals FNIP1, which then opens the gate, allowing TFEB into the cell’s nucleus. Without FNIP1 receiving the signal from AMPK, TFEB remains trapped outside the nucleus, making mitochondrial breakdown and removal impossible.
“This discovery that FNIP1 is at the heart of the metabolic stress response will help us understand healthy aging, cancerous tumors, neurodegenerative diseases, and so much more. This is a fundamental cellular process that ties into many diseases and will be in textbooks for years to come,” says Shaw, senior author and director of Salk’s Cancer Center.
The study compared unaltered human kidney cells with two altered types of human kidney cells: one that lacked AMPK entirely and another that lacked only the specific parts of FNIP1 that communicate with AMPK. The researchers established that AMPK phosphorylates FNIP1, which enables the protein to mediate signals that allow TFEB into the nucleus.
For future efforts, the team hopes their findings can assist in developing novel therapeutics for the numerous diseases that tie into this fundamental cellular process.