Model Reveals How a Protein Complex Guards the Gateways Inside Mitochondria

Mitochondria work around the clock to convert food into usable energy, and much of this activity takes place along cristae, the deep folds in the mitochondria’s inner membrane. For cristae to function properly, they must hold their shape while tightly regulating which molecules move in and out. Guarding their narrow entrances is a protein complex called MICOS, which stabilizes the pockets and acts as a molecular filter. Disruptions to this system have been tied to neurodegenerative diseases and cancer, but the precise mechanism behind MICOS’s gatekeeping function has not been well understood.

A team led by Evangelia Nathanail at the Max Delbrück Center, and Edoardo Rolando from Freie Universität Berlin, have built a model of the human Mic60-Mic19 subcomplex, a central component of MICOS. Published in Nature Communications, their simulations show how the subcomplex’s flexible structure stretches across the cristae entrance, letting smaller molecules through while keeping larger proteins out. 

The Mic60-Mic19 subcomplex includes a long, disordered region without a fixed shape, which has made it hard to image or model using traditional methods. To build their model, the team first used X-ray crystallography to capture the structure of a section of Mic60 found only in animals, then combined it with fungal structures and AI predictions to construct a virtual model of the human version. Because this initial model was static, the team helped simulate the subcomplex’s movements computationally. Comparing the model to structural data from human mitochondria, the team found 97% correspondence.

To test the gatekeeping function directly, researchers added spheres of varying sizes to the model and found that the subcomplex blocked those with a radius larger than two nanometers, a result driven by its disordered regions. “With one static structure, we might not have seen exactly how it swats all of those spheres away,” says Nathanail. “That’s exactly why we needed an approach to see it in action.”

The researchers also found that a known mutation associated with optic nerve damage and a developmental brain disorder alters the MICOS complex’s core, offering a possible explanation for how that mutation causes disease. Confirming this will require observing the full complex at work inside mitochondria. “We are now looking into the structure of the machinery inside cells, and how it changes during disease and aging,” says Daumke.