Study Finds Mechanisms Responsible for Mitochondrial DNA Nucleoid Distribution

Mitochondria serve as cellular power plants, generating energy while housing their own genome called mitochondrial DNA (mtDNA). Each cell maintains hundreds to thousands of mtDNA copies within nucleoids, protein-DNA clusters spaced evenly along mitochondria. This organization ensures consistent gene expression across the organelle and proper inheritance during cell division.

Mitochondrial and mtDNA dysfunction contributes to serious conditions, including metabolic disorders like liver failure and encephalopathy, as well as aging-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Despite its importance, scientists lacked a clear explanation for how cells achieve such precise nucleoid spacing.

"Proposed mechanisms related to mitochondrial fusion, fission, or molecular tethering cannot explain it, since nucleoid spacing is maintained even when they are disrupted," explains Suliana Manley from EPFL's Laboratory of Experimental Biophysics.

Manley and postdoctoral fellow Juan Landoni identified mitochondrial pearling as the key mechanism. This process temporarily reshapes mitochondria into a beads-on-a-string form, with evenly spaced constrictions that separate and redistribute nucleoid clusters.

Using advanced microscopy techniques—including super-resolution imaging, correlated light and electron microscopy, and phase contrast—the team observed pearling events occurring several times per minute in live cells. The constrictions, or "pearls," match nucleoid spacing distances, with most containing a nucleoid at their center.

During pearling, larger nucleoid aggregates split into smaller units distributed across adjacent pearls. When mitochondria revert to their tubular shape, the nucleoids remain evenly positioned. Calcium entry into mitochondria triggers this reshaping, while internal membrane structures help maintain separation. Interfering with either factor causes nucleoids to clump together. 

"Since Margaret Reed Lewis first sketched mitochondrial pearling in 1915, it has largely been dismissed as an anomaly linked to cellular stress," says Landoni, first author of the paper published in Science. "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.