Mitochondria are the tiny powerpacks that supply most of the energy our cells need. Their ability to generate this energy relies on a distinctive architecture: two membranes, one tucked inside the other, separated by a narrow gap called the intermembrane space (IMS). This tiny space helps sustain the chemistry of energy production, making its organization critical to how these cellular powerpacks function.
Now, a new study led by a University of Ottawa Faculty of Medicine investigator reports a potentially transformative discovery: the volume of the IMS is genetically controlled and adjustable. By controlling where this space expands or narrows within each mitochondrion, cells can actively shape the internal architecture of their powerpacks and tune how they function.
Published in Science Advances , the study identifies SPRIZ—short for 'SPatial Regulator of the mitochondrial Intermembrane Zone'—as a key protein that cells use to shape the internal architecture of their powerpacks.
Its discovery opens a new path to understanding how disruptions in this delicate spacing may contribute to diseases in which mitochondria fail to meet cells' energy needs, or in which damaged powerpacks are not properly maintained or cleared away, as occurs in Parkinson's disease.
SPRIZ: A molecular pillar
Working with collaborators at uOttawa and in the United States, the team combined computer simulations of molecular movement, genetics, large-scale protein analysis and advanced imaging, including three-dimensional electron tomography. Together, these approaches showed how SPRIZ bridges the two mitochondrial membranes, forming a molecular pillar that holds open the space between them.
This ability to connect the membranes while keeping them apart is what makes SPRIZ distinctive, explains Dr. Luca Pellegrini , a full professor in the Faculty's Department of Biochemistry, Microbiology and Immunology who led the study. While many membrane tethers bring membranes close enough to exchange materials, SPRIZ appears to use that connection to maintain a defined spacing.
"What makes SPRIZ so unexpected is that it uses a familiar mechanism—a tether—to do something different: it connects the two mitochondrial membranes while acting as a rigid pillar that holds them a set distance apart, so the room between them keeps a defined height," Dr. Pellegrini explains.
The team put this molecular spacing system to the test: altering it in laboratory experiments substantially changed the size of the IMS. Like adjusting the height of a ceiling, changing these molecular supports reshaped the room within. The findings show that cells have genetic instructions for setting the dimensions of this essential space, giving them control over the internal layout of their powerpacks.
Why a few nanometres matter
Even a tiny change in the room between mitochondrial membranes can change what happens inside it. When the team expanded the IMS, molecules gained greater access to this space, while mitochondrial calcium uptake changed—showing that its dimensions help control how signals reach the machinery within these cellular powerpacks.
"A change of only a few nanometres in the height of that room is enough to slow the calcium that must cross it to reach the reactor," Dr. Pellegrini says.
Experiments in mice revealed just how precisely SPRIZ acts. Removing the gene altered the spacing between mitochondrial membranes while leaving the mitochondria's overall structure intact. The mice remained viable, allowing the team to distinguish a targeted change in the IMS from widespread damage to the powerpacks.
The team also demonstrated that SPRIZ can be used to tailor this space. By engineering a longer version of the molecular pillar, the researchers pushed the membranes farther apart and measured how the expanded IMS affected molecular access and calcium uptake. This ability to tailor the dimensions of the IMS gives researchers a way to test whether different functions within these cellular powerpacks require different amounts of space.
A new dimension in mitochondrial evolution
The team found evidence of the same molecular pillar architecture in humans and every other vertebrate species examined. This shared feature traces back roughly 500 million years: their evolutionary analysis places the emergence of SPRIZ around the origin of vertebrates and found it absent from plants, fungi—including yeast—and invertebrates such as sponges, worms and insects.
For Dr. Pellegrini, this opens a broader perspective on how cellular powerpacks evolved to meet the changing demands of animal life. As animals diversified in body size, tissues and organs, their mitochondria had to support increasingly varied tasks while adapting to fluctuations in nutrient supply and energy needs. The arrival of SPRIZ may have given vertebrate cells an additional way to meet those demands: tailoring the dimensions of the IMS to the work each cell performs.
This places the discovery in a larger evolutionary story—one in which mitochondria adapted not only through changes to their molecular machinery, but also through control over the space in which that machinery works.
Collaborative science
The discovery brought together expertise in mitochondrial metabolism, physiology and evolution. At the uOttawa Faculty of Medicine, collaborators included Drs. Mary-Ellen Harper, Eric Lee, Morgan Fullerton and Yan Burelle. The team also benefited from the contributions of two prominent U.S. scientists: mitochondrial biologist Dr. György Hajnóczky and evolutionary biologist Dr. Eugene Koonin.
"That scientists of this standing chose to join the effort speaks to the importance of the questions this discovery opens up," Dr. Pellegrini says.
At the heart of that effort were his students: Raman Shulinski, Roman Loban and Victoria Caminiti. Their contributions helped turn a question about the smallest dimensions of mitochondria into a discovery with implications across cell biology.
"Raman Shulinski, the first author of this study, is a graduate student, and two of my students who helped carry this work forward are undergraduates," Dr. Pellegrini says. "For young scientists at the start of their careers to play such a central role in a discovery like this shows what our students can accomplish at the University of Ottawa."
Dr. Pellegrini's lab is slated to move into the University of Ottawa's Advanced Medical Research Centre (AMRC) when it opens in 2027. The AMRC, the biggest investment in uOttawa history, will feature 350,000 sq. ft. of advanced research space, with a dozen state-of-the-art core facilities not found anywhere else in the region.
