Mitochondrial protein structure critical for activating ISR revealed

Mitochondria, renowned as the cellular “powerhouses,” are renowned for fueling energy production and upholding overall well-being. However, these organelles also play a critical role in preserving our health. A groundbreaking study by Scripps Research scientists, published in August 2023, has unveiled a significant advancement in comprehending the intricate process of mitochondrial stress signaling.

This research zeroes in on a pivotal mitochondrial protein known as DELE1, which holds the key to triggering the cell’s integrated stress response (ISR)—a fundamental pathway for cellular maintenance. The unique structure of DELE1, which forms an octamer, or an eight-fold complex, consisting of identical protein fragments, has emerged as a central element in this exploration.

The newfound insight into DELE1’s role in activating ISR offers exciting possibilities for potential therapies targeting age-related ailments, such as neurodegenerative diseases, heart conditions, and cancer. The study sheds light on the molecular underpinnings of mitochondrial stress, contributing to a deeper comprehension of its impact on cellular health.

As we age, mitochondria’s capacity to detect and manage stressors diminishes, resulting in reduced energy levels and heightened vulnerability to various challenges. Unveiling the molecular intricacies of this pathway not only enhances our understanding but also paves the way for innovative treatments aimed at mitigating the effects of mitochondrial stress on overall well-being.

“It was a remarkable surprise to observe the formation of this significantly larger oligomeric structure,” comments study co-senior author Gabriel Lander, Ph.D., who is a professor in the Department of Integrative Structural and Computational Biology at Scripps Research. He likens it to two four-legged spiders intertwining their legs to create a flexible cylindrical arrangement.

Through meticulous work, the researchers captured over 12,000 electron microscope images of the octamer and utilized algorithms to generate a comprehensive three-dimensional structural model. By scrutinizing the positions of various amino acids—the essential components of proteins—within the structure, they successfully pinpointed the amino acids involved in binding and assembling the octamer.

To validate the necessity of DELE1’s oligomerization in activating the ISR, the team introduced specific mutations into key amino acids, disrupting DELE1’s ability to bind together. Cultivating cells with this altered, un-oligomerizable form of DELE1 demonstrated an inability to activate the ISR. This emphasizes the critical role of oligomerization in triggering this stress response pathway.

The trajectory ahead involves leveraging this structural insight to manipulate these pathways, particularly in diverse diseases and disorders, according to the researchers.

“The understanding that oligomerization could be a regulatory focal point provides us with a foundation for potential drug development,” remarks co-senior author Luke Wiseman, Ph.D., a professor in the Department of Molecular Medicine at Scripps Research. He adds, “We believe that targeting this pathway holds promise for enhancing outcomes across various disorders.”

In addition to Jie Yang, Kelsey Baron, Luke Wiseman, and Gabriel Lander, the authors of the study titled “DELE1 oligomerization promotes integrated stress response activation” encompass Daniel E. Pride, Anette Schneemann, Wenqian Chen, and Albert S. Song from Scripps Research, along with Xiaoyan Guo, Giovanni Aviles, and Martin Kampmann from the University of California, San Francisco.

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