‘Pearling’ Trick Inside Cells Solves Long-Standing Mystery of How Mitochondria Distribute DNA

Scientists at the École Polytechnique Fédérale de Lausanne have discovered that mitochondria, the energy-producing organelles inside cells, distribute their genetic material through a previously unknown process that resembles the formation of pearls along a string — a mechanism the researchers named mitochondrial pearling. The finding, published Thursday in the journal Science, resolves a long-standing puzzle in cell biology about how each daughter cell reliably receives mitochondria containing functional copies of mitochondrial DNA when a cell divides, and has immediate implications for understanding and potentially treating mitochondrial diseases, a category of disorders affecting at least one in 5,000 people.

Mitochondria carry their own small genome, a circular DNA molecule approximately 16,500 base pairs long that encodes 13 proteins essential for oxidative phosphorylation, the chemical process by which mitochondria generate the ATP that powers cellular functions. Unlike nuclear DNA, which is carefully duplicated and parceled into daughter cells through the elaborate machinery of mitosis, mitochondrial DNA was believed to be distributed relatively passively when the mitochondrial network fragmented during cell division. Researchers had observed that mitochondria within cells form a dynamic, interconnected tubular network that constantly fuses and divides, and assumed this mixing was sufficient to distribute DNA to daughter organelles. But careful quantitative studies had shown that DNA distribution was more reliable than chance mixing would predict, suggesting an active mechanism was at work.

The EPFL team used a combination of live-cell super-resolution microscopy and genome-level tracking with fluorescent tags on individual mitochondrial DNA molecules to observe what actually happens to DNA during cell division. They found that in the hours before a cell divides, the elongated tubular mitochondrial network undergoes a structured transformation in which DNA nucleoids — the discrete, protein-bound packages in which mitochondrial DNA is organized — move to regularly spaced positions along the mitochondrial tubules. The spaces between nucleoids then constrict, creating a beaded or pearl-like morphology in which each bead contains one or more DNA copies. When the cell subsequently divides and the mitochondrial network fragments, the fragmentation preferentially occurs in the constricted regions between nucleoids, ensuring that each fragment carries genetic material.

The pearling process was found to be regulated by specific proteins in the mitochondrial outer membrane that interact with the cytoskeleton of the cell. Disrupting these proteins caused random DNA distribution, resulting in daughter cells with highly unequal mitochondrial DNA copies — a condition that impairs cellular energetics. The researchers identified the protein MIEF2, previously known to regulate mitochondrial fission, as a key coordinator of the pearling process.

For mitochondrial disease research, the finding identifies new potential therapeutic targets. Many mitochondrial diseases result from mutations in mitochondrial DNA that accumulate heteroplastically — meaning cells contain a mixture of normal and mutant copies. Whether a patient develops symptoms often depends on the fraction of mutant copies that exceed a threshold. Understanding how mitochondrial DNA distribution is controlled opens the possibility of interventions that could shift the heteroplasmy ratio toward lower mutant fractions.