Glutaminase filaments: A New Perspective on Mitochondrial Dynamics and Mitophagy Protection

We are thrilled to share our most novel research, “Molecular Mechanism of Glutaminase Activation through Filamentation and its Impact on Mitophagy Protection,” published in Nature Structural and Molecular Biology in October 2023 (DOI: 10.1038/s41594-023-01118-0).

Our investigation centers on glutaminase (GLS), a pivotal mitochondrial enzyme that transforms glutamine into glutamate and the main research subject in our lab for the past 15 years. GLS is essential for synthesizing amino acids, nucleotides, and other critical molecules, fueling rapidly dividing cells and facilitating key metabolic pathways such as ammoniagenesis and gluconeogenesis. GLS’s activity is intricately regulated through allosteric mechanisms, covalent modifications, and protein interactions.

Historically, the activation of GLS was thought to be solely through the stabilization of its active tetrameric form. Our research, however, introduces a novel paradigm: inorganic phosphate (Pi) induces GLS to form filaments, thereby enhancing enzyme efficiency and substrate turnover. This discovery opens new avenues for understanding how Pi binding initiates GLS filamentation and its biological significance.

Utilizing single-particle cryogenic-electron microscopy, we have unveiled the structure of GLS filaments and the sophisticated mechanism by which Pi binding facilitates enzyme activation and filament formation. Our study further reveals that cells under glutamine starvation, which exhibit GLS filaments within their tubular mitochondria, show increased resistance to mitochondrial fission and a reduced propensity for mitophagy.

Moreover, we have identified GLS helical filaments in the mitochondrial matrix of nutrient-deprived cells, establishing a direct link between metabolic enzyme structural changes and mitochondrial remodeling, dynamics, and survival. These insights are crucial for understanding mitochondrial function, recycling, and nutrient response, potentially impacting diseases associated with mitophagy dysfunction.

In essence, our research illuminates the complex interplay between GLS filamentation and mitochondrial behavior, marking a significant advancement in our comprehension of cellular metabolism and homeostasis. This study not only highlights the importance of GLS in cellular survival and mitochondrial dynamics but also sets the stage for future explorations into metabolic enzymes and their roles in health and disease.

Many thanks to the outstanding group of researchers involved in this work.

Douglas Adamoski, Marilia M Dias, Jose Edwin N Quesñay, Zhengyi Yang, Ievgeniia Zagoriy, Anna M Steyer, Camila T Rodrigues, Alliny CS Bastos, Bianca N Silva, Renna KE Costa, Flávia MO Abreu, Zeyaul Islam, Alexandre Cassago, Marin G van Heel, Sílvio R Consonni, Simone Mattei, Julia Mahamid, Rodrigo V Portugal, Andre LB Ambrosio, and Sandra MG Dias (2024) Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection. Nature Structural & Molecular Biology 30, 1902-1912.

alba /// February 17, 2024