A strange bead-like motion inside cells may be the secret to keeping their DNA—and health—in balance.
Mitochondria are often described as the power plants of the cell because they produce the energy cells need to survive. To support this role, they carry their own small set of genetic instructions called mitochondrial DNA (mtDNA).
Inside each cell, there are hundreds to thousands of copies of mtDNA. These copies are grouped into compact clusters known as nucleoids. Researchers have long observed that nucleoids are arranged at regular intervals within mitochondria. This orderly pattern helps ensure that mtDNA is properly inherited when cells divide and that its genes are expressed evenly throughout the mitochondria.
Why Mitochondrial DNA Organization Matters
When mitochondria or their DNA do not function correctly, the effects can be widespread. Disruptions have been linked to metabolic and neurological conditions such as liver failure and encephalopathy, as well as age-related diseases including Alzheimer’s and Parkinson’s.
Given how critical mtDNA is, scientists have been trying to understand how cells maintain such precise spacing of nucleoids. Until now, this question has remained unresolved.
“Proposed mechanisms related to mitochondrial fusion, fission, or molecular tethering cannot explain it, since nucleoid spacing is maintained even when they are disrupted,” says Suliana Manley, professor at the Laboratory of Experimental Biophysics (LEB) at EPFL.
Discovery of Mitochondrial Pearling
Manley, together with Juan Landoni, a postdoctoral fellow at the LEB, has now identified the mechanism responsible for distributing mtDNA. Their findings point to a process called “mitochondrial pearling,” which had previously been overlooked.
During this temporary transformation, mitochondria adopt a shape that resembles beads on a string. This structural change helps break apart clusters of mtDNA and spread nucleoids more evenly along the mitochondria, maintaining consistent spacing.
Imaging Mitochondria in Living Cells
To study this process in detail, the researchers used a combination of advanced microscopy techniques to observe mitochondria and their DNA inside living cells. These methods included super-resolution imaging and correlated light and electron microscopy, along with gentler approaches such as phase contrast microscopy.
Using these tools, the team was able to follow individual nucleoids, capture rapid shifts in mitochondrial shape, and better understand how their internal structure is organized.
What Happens During Pearling
Live-cell imaging showed that pearling events can occur several times per minute. During these moments, mitochondria briefly form a series of evenly spaced constrictions along their length. The distance between these bead-like sections closely matches the usual spacing between nucleoids.
Most of these “pearls” contain a nucleoid near the center, although the structures can also form without mtDNA.
As the process continues, larger nucleoid clusters often split into smaller groups that settle into neighboring pearls. Once the mitochondrion returns to its normal tubular shape, the nucleoids remain separated, preserving their regular distribution.
What Controls Mitochondrial Pearling
The researchers also identified factors that regulate this process. Through genetic and pharmacological experiments, they found that calcium entering the mitochondria can trigger pearling. Internal membrane structures also help maintain the separation of nucleoids.
When either of these regulatory elements is disrupted, nucleoids tend to clump together instead of remaining evenly spaced.
A Rediscovered Cellular Mechanism
“Since Margaret Reed Lewis first sketched mitochondrial pearling in 1915, it has largely been dismissed as an anomaly linked to cellular stress,” says Landoni. “Over a century later, it is emerging as an elegantly conserved mechanism at the heart of mitochondrial biology. This biophysical process offers a simple and energy efficient means to distribute the mitochondrial genome.”
Implications for Disease and Future Research
The findings highlight how cells rely on both physical processes and molecular systems to maintain order. Understanding how mitochondrial pearling works and how it is controlled could provide important insight into diseases linked to mtDNA.
This knowledge may also help guide future strategies for treating conditions associated with mitochondrial dysfunction.
Reference: “Pearling drives mitochondrial DNA nucleoid distribution” by Juan C. Landoni, Matthew D. Lycas, Josefa Macuada, Willi Stepp, Roméo Jaccard, Christopher J. Obara, Andrew S. Moore, David Hoffman, Jennifer Lippincott-Schwartz, Wallace Marshall, Gabriel Sturm and Suliana Manley, 2 April 2026, Science.
DOI: 10.1126/science.adu5646
Other Contributors
- Pontificia Universidad Católica de Chile
- Howard Hughes Medical Institute
- University of California, San Francisco
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