Mitochondria are sometimes called the powerhouses of the cell because they produce the energy the cell needs to function. To support this role, they retain their own genetic material known as mitochondrial DNA (mtDNA).
Each cell holds hundreds to thousands of copies of mtDNA. These copies are grouped into compact structures called nucleoids. Scientists have long observed that these nucleoids are arranged in a regular pattern within mitochondria. This organization helps ensure that mtDNA is inherited when cells divide and that its genes are expressed uniformly throughout the mitochondria.
If mitochondria or their DNA do not function properly, the effects can be severe. This disorder is thought to be associated not only with aging-related diseases such as Alzheimer’s disease and Parkinson’s disease, but also with metabolic and neurological diseases such as liver failure and encephalopathy.
A long-standing mystery in cell biology
Given how important mtDNA is, researchers have sought to understand how cells maintain such consistent spacing of their nucleoids. The answer remains unclear.
“Proposed mechanisms involving mitochondrial fusion, fission, and molecular binding cannot explain this, as the nucleoid spacing is maintained even when disrupted,” says Suriana Manley, professor at EPFL’s Laboratory of Experimental Biophysics (LEB).
Manley and her colleague, LEB postdoctoral fellow Juan Landoni, have now identified the mechanism responsible. Their research points to a process called mitochondrial pearl formation that has received little attention so far.
Mitochondrial purling is a temporary shape change in which mitochondria form a bead-like structure on a thread. During this transformation, clusters of mtDNA are separated and redistributed. This allows the nucleoids to spread out more evenly and maintain regular spacing.
Observe mitochondrial behavior
To study this process, the researchers combined advanced imaging techniques to observe mitochondria and their DNA inside living cells. These include super-resolution imaging, correlative light and electron microscopy, and phase contrast microscopy.
Using these tools, the team was able to track individual nucleoids, capture rapid changes in mitochondrial shape, and better understand how the internal structure is organized.
what happens during pearling
Live cell imaging showed that nacreous events can occur several times per minute. At these moments, mitochondria temporarily form evenly spaced constrictions along their length. The distance between these “pearls” roughly corresponds to the normal spacing between nucleoids.
Most of these bead-like sections contain a nucleoid near the center, but structures can also form in the absence of mtDNA.
As this process continues, large clusters of nucleoids often split into smaller groups and colonize adjacent pearls. As the mitochondria return to their normal tubular shape, the nucleoids remain separated and maintain a uniform distribution.
what controls the process
The researchers also investigated what promotes and regulates pearl diving. Through genetic and pharmacological experiments, they discovered that calcium entering the mitochondria can trigger this process. Additionally, the internal membrane structure helps maintain nucleoid separation.
When these regulatory factors are disrupted, nucleoids tend to aggregate rather than remain evenly spaced.
Rediscovered features of mitochondria
“Ever since Margaret Read Lewis first sketched mitochondrial pearl formation in 1915, mitochondrial pearl formation has been largely ignored as an abnormality related to cellular stress,” Landoni says. “After more than a century, it is emerging as an elegantly conserved mechanism at the heart of mitochondrial biology. This biophysical process provides a simple and energy-efficient means to distribute mitochondrial genomes.”
Why is this discovery important?
This finding shows that cells rely not only on complex molecular systems but also on physical processes to maintain their organization. Understanding how mitochondrial pearl formation functions and is regulated may provide important insights into mtDNA-related diseases.
This knowledge could ultimately help guide new approaches to treating conditions associated with mitochondrial dysfunction.
other contributors
- Pontifical Catholic University of Chile
- Howard Hughes Medical Institute
- University of California, San Francisco
