Protein Uncovered as Critical Link in Mitochondrial Repair

Scientists at Salk Cancer Center have uncovered that the protein FNIP1 plays a critical role in a cell sensing low energy levels and eliminating and replacing damaged mitochondria. The findings may help researchers understand and provide more insights into healthy aging, cancerous tumors, neurodegenerative disease, and other conditions linked to the mitochondria.

The new study is published in Science in an article titled, “Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.”

Reuben Shaw, PhD, senior author and director of Salk’s Cancer Center, has spent nearly two decades piecing together such clues to understand the cellular response to metabolic stress, which occurs when cellular energy levels dip.

Shaw and his team cracked the case on this process of removal and replacement and discovered FNIP1.

“This is a final puzzle piece that connects decades of studies from labs all over the world. It solves one of the final mysteries about how the signal to make new mitochondria is tied to the original signal that energy levels are low,” said Shaw.

“Many years ago, we suspected the FNIP1 protein might be important for AMPK-TFEB communication that led to mitochondria synthesis and replacement in the cell during metabolic stress, but we didn’t know how FNIP1 was involved,” said first author Nazma Malik, PhD, a postdoctoral fellow in Shaw’s lab. “If correct, this finding would finally link AMPK and TFEB, which would both enrich our understanding of metabolism and cellular communication and provide a novel target for therapeutics.”

To determine whether 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 AMPK talks to. The team discovered that AMPK signals FNIP1, which then opens the gate to let TFEB into the nucleus of the cell. Without FNIP1 receiving the signal from AMPK, TFEB remains trapped outside the nucleus, and the entire process of breaking down and replacing damaged mitochondria is not possible. And without this robust response to metabolic stress, our bodies—along with the many plants and animals whose cells also rely on mitochondria—would not be able to function effectively.

“Watching this project evolve over the last 15 years has been a rewarding experience,” said Shaw. “I am proud of my dedicated, talented team, and I cannot wait to see how this monumental finding will influence future research—at Salk and beyond.”

Previous articleNovel Biomarker and Potential Improved Therapy for Multiple Sclerosis and Related Neurological Disorders
Next articleCelebrating DNA: Matthew Cobb’s Reflections on the Double Helix