Scientists often act like detectives, piecing together clues that on their own may seem meaningless, but together they solve the case. Professor Reuben Shaw has spent almost two decades putting together these clues to understand the cellular response to metabolic stress, which occurs when cellular energy levels drop. Whether energy levels drop because the cell’s powerhouses (mitochondria) are failing or because the supplies needed to produce energy are lacking, the answer is the same: get rid of damaged mitochondria and create new ones.
Now, in a study published in Science On April 20, 2023, Shaw and his team settled the case for this removal and replacement process. It turns out that a protein called FNIP1 is the critical link between a cell sensing low energy levels and removing and replacing damaged mitochondria.
“This is a final piece of the puzzle that connects decades of studies from laboratories around the world. It solves one of the final mysteries about how the signal to produce new mitochondria is linked to the original signal that energy levels are low.” says Shaw, lead author and director of the Salk Cancer Center. “This discovery that FNIP1 is at the heart of the metabolic stress response will help us understand healthy aging, cancerous tumors, neurodegenerative diseases, and much more. This is a fundamental cellular process that is linked to many diseases and will be in textbooks for years to come.”
Nearly 15 years ago, Shaw’s lab discovered that an enzyme called AMPK was responsible for starting the process of removing damaged mitochondria. Later, the team showed that one part of this removal process is that the cell breaks damaged mitochondria into hundreds of fragments, and then sorts those fragments to remove the damaged parts and reuse the functional parts. But the question remained: how is the repair of damaged power plants connected to the signal to start making new power plants from scratch?
When mitochondria are damaged, or when sugar (glucose) or oxygen levels drop in the cell, energy levels drop rapidly. After a drop in energy as small as 10 percent, AMPK kicks in. AMPK communicates with another protein, called TFEB, to tell genes to make 1) lysosomes (cellular recycling centers) to remove damaged mitochondria and 2) replacement mitochondria. But it was not clear how AMPK and TFEB communicated.
When a new suspect, FNIP1, joined the mystery of metabolic stress, the answer was finally within reach. FNIP1 is the most recently discovered protein of the AMPK, TFEB, FNIP1 trio. For years, researchers were only able to link FNIP1 to AMPK, and therefore thought it might be a red herring or red herring; instead, it was the clue that solved the case.
“Many years ago, we suspected that the FNIP1 protein might be important for AMPK-TFEB communication that led to the synthesis and replacement of mitochondria in the cell during metabolic stress, but we did not know how FNIP1 was involved,” says first author Nazma. Malik, a postdoctoral fellow in Shaw’s lab. “If correct, this finding would ultimately link AMPK and TFEB, enriching our understanding of cellular metabolism and communication and providing a novel target for therapy.”
To determine if FNIP1 was the missing link between AMPK and TFEB, the researchers 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 they matched. AMPK communicates. The team found that AMPK signals FNIP1, which then opens the gate to allow TFEB to enter the cell’s nucleus. Without FNIP1 receiving the AMPK signal, TFEB remains trapped outside the nucleus, and the entire process of breaking down and replacing damaged mitochondria is not possible. And without this robust metabolic stress response, our bodies—along with many plants and animals whose cells also rely on mitochondria—wouldn’t be able to function effectively.
“Watching this project evolve over the past 15 years has been a rewarding experience,” says Shaw, William R. Brody Professor. “I am proud of my dedicated and talented team, and I can’t wait to see how this monumental find will influence future research, at Salk and beyond.”
Other authors include Bibiana I. Ferreira, Pablo E. Hollstein, Stephanie D. Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S. Shadel, and Uri . Salk Institute Mansion.
The work was supported by the National Institutes of Health (R35CA220538, P01CA120964, R01DK080425, NCI CCSG P30 CA014195 and R21 DC018237), the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), an American Heart Association, and the Paul G. Allen Frontiers Group Award (19PABH134610000), The Salk Institute National Cancer Institute Cancer Center (CCSG P30 CA014195) and the Nathan Shock Center for Research on Aging (P30 AG068635), The Waitt Foundation, The Foundation National Sciences (NeuroNex Award 2014862) and the Glenn Foundation.
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