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Structural basis of mitochondrial inner membrane shape and dynamic

Final Report Summary - MITOSHAPE (Structural basis of mitochondrial inner membrane shape and dynamic)

In the ERC project MitoShape, my group explored how the shape of mitochondria is generated and maintained. Mitochondria constitute the site of cellular energy production. They are elongated, tubular structures that are delineated from the cellular interior by an outer mitochondrial membrane. An inner mitochondrial membrane folds inwards to create large bag-like invaginations that harbor the enzymes required for energy production. These membrane invaginations do not form spontaneously, they are bent to shape by complex cellular protein machineries. Alterations of these proteins, for example by mutations, can affect the functionalities of these machineries so that the inner mitochondrial membrane is not correctly folded. Such folding defects are hallmarks of neurodegenerative diseases, for example in Parkinson’s or Alzheimer's disease or in degenerations of the optical nerve. In this ERC grant, my group examined the three dimensional structure of proteins that are responsible for shape generation of the inner mitochondrial membrane.

In work package 1 (WP1), the structure of the motor protein Mgm1 was determined, which is crucial for shaping the inner mitochondrial membrane. We found that Mgm1 consists of four distinct domains: An elongated paddle-like structure mediates the binding to the mitochondrial inner membrane. A motor domain allows the movement of a lever-like structure under consumption of cellular energy. Finally, a stalk-shaped structure mediates Mgm1 assembly into a filament. Based on the Mgm1 structure, we performed functional experiments that eventually resulted in a model of how Mgm1 filaments assemble at the inner mitochondrial membrane and reshape it. We also obtained initial hints of how mutations in the related OPA1 GTPase can lead to neurodegenerative disease (Fälber et al, Nature 2019). In addition to this study, we examined structures of the Mgm1-related dynamin3 GTPase (Reuboldt et al, Nature 2015) and the EHD4 ATPase (Melo et al, PNAS 2017) in WP1. These studies revealed common principles of how these types of molecular motors work. For example, they have a closed, inactive conformation and become only activated when they are recruited to their specific cellular sites of action.

In WP2, we explored the structure of another cellular machinery that localizes to the neck of the inner mitochondrial membrane invaginations, the MICOS complex. We identified a membrane-binding site in MICOS and showed that it is crucial for generating the membrane neck. We also characterized the molecular basis of how two proteins of the MICOS complex interact and demonstrated that the interaction stimulates the membrane remodeling activity of MICOS (Hessenberger...Kunz...Daumke Nature Communication 2017). Currently, we analyze the structural details of how this is achieved.

WP3 aimed to delineate how the MICOS complex interacts with Mgm1 and with another cellular machinery of the outer mitochondrial membrane. However, we were not able to reproduce these published interactions with purified proteins. Instead, we focused on the structural characterization of a protein that is involved in the degradation of mitochondria, FIP200. We found that a ‘Claw’-shaped structure in FIP200 is crucial for recognizing FIP200 cargo to be degraded, via a cellular adaptor protein. In this way, our study provided the structural framework to understand FIP200 function during mitochondrial degradation (Turco et al., Mol Cell 2019).

A more detailed description of our ERC results is available in several press releases that address a scientifically interested lay audience:

Bent to the task: New dynamin structure reveals how it wraps around membranes, https://www.mdc-berlin.de/news/news/bent-task-new-dynamin-structure-reveals-how-it-wraps-around-membranes

The art of folding mitochondrial membranes, https://www.mdc-berlin.de/news/2017/the-art-of-folding-mitochondrial-membranes

How proteins reshape cell membranes, https://www.mdc-berlin.de/news/news/how-proteins-reshape-cell-membranes

Keeping a cell's powerhouse in shape, https://www.mdc-berlin.de/news/press/dynamin-mgm1-mitochondria-cells

How cells devour themselves, https://www.mdc-berlin.de/news/news/how-cells-devour-themselves