Flexible protein gate controls access to mitochondrial folds, simulations suggest

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Twenty-four hours a day, seven days a week, mitochondria in our cells churn out energy from the food we eat, which keeps our bodies functioning. Much of this work happens along cristae—deep pockets in the mitochondria's inner membrane.

To work properly, cristae must maintain their shape while carefully controlling which molecules enter and exit. At their narrow entrances sits a protein complex called MICOS, which helps stabilize these pockets and acts as a molecular filter. When this architecture is disrupted, the consequences can include neurodegenerative diseases and cancer.

But exactly how MICOS works has remained unclear. A team led by Evangelia Nathanail, a doctoral student in the Structural Biology of Membrane-Associated Processes lab of Dr. Oliver Daumke at the Max Delbrück Center, and Edoardo Rolando, also a doctoral student in the lab of Dr.

Cecilia Clementi at Freie Universität Berlin, has now modeled the human Mic60-Mic19 subcomplex, a central part of MICOS. Their simulations, which were published in Nature Communications, show how its flexible structure spans the cristae entrance, allowing smaller molecules to pass through while blocking larger proteins. "Our study not only reveals the molecular architecture of an essential cellular machine, but it also shows how one can model highly dynamic protein complexes that escape traditional structural biology methods," says Daumke, co-senior author of the study.

MICOS is made up of multiple copies of several proteins. Its largest component, the Mic60-Mic19 subcomplex, contains a long, disordered region—a flexible stretch with no fixed shape. This flexibility is one reason it has been difficult to image or model.

To build their model, the team combined several approaches. They first used X-ray crystallography to capture the structure of a section of Mic60 found only in animals. They combined this structure with fungal structures and AI predictions to build a virtual model of the human version.