Mitochondria are often described as the cell's power plants, because they generate energy. To help them achieve this, mitochondria carry their own small genome called mitochondrial DNA (mtDNA).
Each cell contains hundreds to thousands of copies of mtDNA, packaged into clusters known as nucleoids. Scientists have known that nucleoids are regularly spaced inside mitochondria. This pattern ensures that mtDNA is passed down when cells divide and that genes on mtDNA are uniformly expressed along mitochondria.
Problems with the function of mitochondria and mtDNA can have far-reaching consequences for the health of the cell and the organism as a whole. They are linked to metabolic and neurological diseases like liver failure and encephalopathy or associated with aging and neurodegenerative diseases like Alzheimer's and Parkinson's.
Having established the importance of mtDNA for the proper function of mitochondria, a key question has remained unanswered: how do cells achieve such precise and robust spacing of nucleoids?
"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.
Now, Manley has led a study with Juan Landoni, postdoctoral fellow at the LEB, that has identified the mechanism behind mtDNA distribution: a previously underestimated phenomenon known as "mitochondrial pearling". This is a transient transformation during which mitochondria take on a "beads-on-a-string" appearance. This helps separate clusters of mtDNA and redistribute nucleoids, ensuring remarkably uniform spacing.
Watching mitochondria in action
To investigate the phenomenon, the researchers combined a broad range of advanced microscopy techniques to observe mitochondria and their DNA inside cells. These included super‑resolution imaging and correlated light and electron microscopy, alongside gentle imaging methods such as phase contrast microscopy. Together, these tools allowed the team to track individual nucleoids, capture rapid changes in mitochondrial shape, and resolve the underlying structural organization.
What happens during pearling
Live‑cell imaging revealed that pearling can occur a few times per minute in cells. During these events, mitochondria temporarily form a series of evenly spaced constrictions. Notably, the spacing between these "pearls" closely matches the typical distance between nucleoids. Most pearls contain a nucleoid near their center, although pearls can also form independently of mtDNA.
As pearling progresses, larger nucleoid clusters often split into smaller units that occupy neighboring pearls. After the mitochondrion returns to its tubular shape, redistributed nucleoids can remain separated—establishing the characteristic regular spacing.
What controls the process
The researchers also identified key regulators of pearling. Using genetic and pharmacological approaches, they revealed that calcium entering the mitochondria can trigger the process. Internal membrane structures can help preserve nucleoid separation. When either mechanism is disrupted, nucleoids clustered into aggregates instead of remaining evenly distributed.
An overlooked jewel of mitochondrial dynamics
"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."
The study shows that cells can harness physical phenomena along with molecular machinery. Understanding this mechanism and its regulation provides invaluable insight into understanding what drives mtDNA-related diseases and may help guide future therapeutic strategies.
Other contributors
- Pontificia Universidad Católica de Chile
- Howard Hughes Medical Institute
- University of California, San Francisco
Reference
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, Suliana Manley. Pearling drives mitochondrial DNA nucleoid distribution. Science 02 April 2026. DOI: 10.1126/science.adu5646
