MitoScanner: Searching for the Right Place to Divide Mitochondria

Proteins DRP1 and MID49 scan the mitochondrial outer membrane before division, revealing a previously unrecognized step in mitochondrial fission

Mitochondria constantly divide and fuse to adapt to the changing needs of cells. Although the protein DRP1 is known to drive mitochondrial division, its mechanism to identify division sites remains unclear. Researchers at the University of Cologne and the Max Planck Institute of Biophysics recently discovered that, before division takes place, DRP1 scans the organelle together with its partner, MID49. Their findings, published in Nature Cell Biology, reveal a previously unrecognized surveillance step in mitochondrial fission, called MitoScanner, and provide new insight into how cells maintain healthy mitochondrial networks.

Text: Cristiana Zollo, Pamela Ornelas

Mitochondria are essential for cellular energy production, but in order to meet the changing needs of the cell, they constantly reshape themselves through cycles of fusion and fission. This balance between merging and dividing the organelle is critical for cellular health, as disruptions have been linked to ageing, neurodegenerative disorders, cardiovascular disease and cancer. At the center of mitochondrial division, a protein called DRP1 assembles at specific sites on the mitochondrial surface, wraps around the organelle and physically constricts it until it separates into two daughter mitochondria. Yet, for years, a question remained unanswered:

How does DRP1 know the right place to cut?

Using advanced live-cell super-resolution microscopy, a technique that uses fluorescence to track individual particles in living cells in real time, researchers from the University of Cologne and the Department of Membrane Dynamics at the Max Planck Institute of Biophysics, led by Prof. Ana García-Sáez, followed individual DRP1 assemblies in with unprecedented detail. Their observations revealed a surprising step and an unknown surveillance process that takes place before division begins.

DRP1 is bound to the mitochondrial outer membrane by its adaptor protein MID49, which acts as a molecular bridge to the organelle. Although they were previously though to appear directly at future division sites, the new findings show that DRP1 and MID49 form mobile assemblies that travel in characteristic helical trajectories along the tubular membrane, exploring the surface of the organelle before division occurs. This process continues until DRP1 assemblies encounter a pre-constricted region, where they accumulate and eventually mediate mitochondrial division.

For Cristiana Zollo, the doctoral researcher behind the work, the findings came as a surprise: “DRP1 was moving across the mitochondrial surface, as if searching for something”, says Zollo. “Once we realized the behavior was consistent, it was clear we had discovered a step in the division process that hadn’t been noticed before. We named the process the ‘MitoScanner’, because the proteins seem to scan the surface in search of future division sites.”

Additionally, the researchers noted that DRP1 does not immediately disappear after division. Instead, some DRP1 assemblies remain at the edges of the newly formed daughter mitochondria and continue to rotate, suggesting that membrane’s shape influences DRP1’s behavior. To better understand this, the experimental results were combined with computational simulations that showed that the curvature of mitochondria influences how the DRP1 assemblies move and where they accumulate, providing a biophysical explanation for the patterns observed in living cells.

Simultaneously, back in the lab, mitochondrial division became inefficient in cells in which DRP1 activity had been reduced, which resulted in long, undivided, mitochondrial networks. This effect is proof that the scanning process itself is biologically important. It also points at MID49 having a larger role in regulating mitochondrial dynamics.

"Mitochondrial division is more than just cutting membranes in two" says Ana García-Sáez. "The textbook view of mitochondrial fission began with the recruitment of DRP1 directly to future division sites, but we now show that an important step comes before that. Our work reveals a previously hidden level of control and establishes the MitoScanner as a fundamental step in mitochondrial division."

In their recent publication, the researchers highlight that mitochondrial division is not a single event, but a complex process of searching, detecting and executing. MitoScanner offers new insights in mitochondrial division. By understanding how DRP1 finds the right place to divide, scientists can better explain how cells maintain healthy mitochondrial networks and adapt to changing needs. However, there is still more to uncover. The question remains on how does DRP1 know where to stop exploring and initiate division. Because defects in mitochondrial dynamics are linked to many human diseases, understanding how the MitoScanner works could open new opportunities to manipulate mitochondrial behavior in neurodegenerative disorders, cardiovascular disease and cancer.