The Role of FNIP1 in Mitochondrial Quality Control

Mitochondria are responsible for cellular energy production, and damaged mitochondria can cause cellular metabolic stress. The cellular response to metabolic stress involves the removal and replacement of damaged mitochondria. A new study published in the journal Science shows that FNIP1 is a protein that is important in linking the cell’s perception of low energy levels and elimination, and replacing damaged mitochondria. The research provides insights into cell communication and metabolism and opens new avenues for therapeutic targets.

Understanding the Cellular Response to Metabolic Stress

For nearly 20 years, Salk Cancer Center director and senior author Professor Reuben Shaw has been researching how cells react to metabolic stress. Damaged mitochondria are removed and new ones are created when cellular energy levels drop. The cellular response is the same whether the energy loss is brought on by malfunctioning mitochondria or a shortage of essential energy sources.

Shaw’s lab found about 15 years ago that an enzyme named AMPK was in charge of starting the clearance of damaged mitochondria. The team then demonstrated how cells divided the mitochondria into hundreds of pieces and examined each one to remove faulty components and restore function. However, it is still unknown how much harm mitochondria cause to the signals that create brand-new energy from scratch.

The Role of FNIP1 in the Cellular Response to Metabolic Stress

When sugar or oxygen levels in cells drop, energy levels drop dramatically and AMPK fires. AMPK binds to another protein called TFEB and instructs the gene to create lysosomes to remove damaged mitochondria and create new ones. However, how AMPK and TFEB interacted was unclear.

Researchers have discovered that FNIP1 is the missing link between AMPK and TFEB. They compared unaltered human kidney cells to two altered human kidney cell types. One completely lacks AMPK and the other lacks only the specific part of FNIP1 that AMPK interacts with. The research team found that AMPK signals FNIP1 and opens the gate, allowing TFEB to enter the cell nucleus. In the absence of FNIP1 signaling from AMPK, TFEB remains outside the nucleus and the entire process of destruction and replacement of damaged mitochondria is not possible.

Significance of the Study

Insights into cellular communication and metabolism are provided by the study’s findings. Shaw, who led the study, explains that this discovery connects decades of research from various laboratories worldwide and solves one of the last mysteries about how the signal to produce new mitochondria is related to the initial signal that energy levels are low. He believes that this fundamental cellular process, which is now part of textbooks, ties into various diseases like healthy aging, neurodegenerative diseases, and cancerous tumors. The study’s findings also reveal new therapeutic targets. Malik, the study’s first author and a postdoctoral fellow in Shaw’s lab, suggests that if the finding is correct, it would finally link AMPK and TFEB, which would enrich our understanding of metabolism and cellular communication and provide a novel target for therapeutics.

Missing Link and Novel Targets

The study published in Science on April 20, 2023, provides insights into the cellular response to metabolic stress. FNIP1, a protein, is the missing link between AMPK and TFEB, and it is responsible for the removal and replacement of damaged mitochondria. The study findings provide insights into cellular communication and metabolism and open new avenues for therapeutic targets.

Study DOI: 10.1126/science.abj5559

Engr. Dex Marco Tiu Guibelondo, BS Pharm, RPh, BS CpE

Editor-in-Chief, PharmaFEATURES