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An international research team led by Professor Duan Liting from the Department of Biomedical Engineering at The Chinese University of Hong Kong (CUHK), in collaboration with Professor Michael M. Kozlov of Tel Aviv University in Israel, has unraveled the physical mechanism behind how mitochondria – the human cell’s vital organelles for energy generation – undergo “pearling” shape transformation when mechanically stretched.

Published in the prestigious international journal Proceedings of the National Academy of Sciences (PNAS), the study reveals that this shape-shifting process serves two vital biological functions of reorganising mitochondrial DNA (mtDNA) and promoting mitochondrial division, thus aiding in maintaining a healthy mitochondrial population in a cell.

Overcoming a century-old biological puzzle with a double-membrane structure

Mitochondria are best known as the cell’s power plants, while they are also restless shape-shifters that split, merge and stretch within seconds. One of their most unusual transformations is “pearling”, where mitochondrion as a smooth tubular structure reorganises into a series of round bulges (“pearls”) strung along thin tethers, resembling a pearl necklace. Although first documented in 1915, the precise physical mechanism driving this unique transformation has remained unclear.

While decades-old physical models successfully describe pearling in single-membrane tubes, they fail to explain this behavior in mitochondria, whose complex double-membrane architecture requires an entirely new framework. A mitochondrion features a complex double-membrane architecture: a smooth outer membrane enveloping an extensively folded inner membrane (cristae) which occupies a substantial part of its internal volume.

Light-driven breakthrough in the lab: revealing mitochondrion inner membrane resistance

To directly investigate how mechanical tension drives pearling, the team employed an innovative optogenetic technique developed in Professor Duan’s Lab. By using blue light to recruit motor proteins to the outer mitochondrial membrane in living cells, they generated precise pulling forces that stretched the mitochondria along their long axis without physical contact.

The study showed that mechanical stretching alone was sufficient to rapidly induce pearling in tubular mitochondria, with longer and more elongated mitochondria tending to produce more pearls. Conversely, when the outer membrane was drawn away from the inner membrane, forming a thin tube composed only of the outer membrane, the tube simply became longer and thinner under tension but never pearled.

The researchers developed a novel physical model explaining that the densely folded inner cristae resist compression. Under tension, this resistance prevents uniform thinning, forcing the outer membrane and internal volume to redistribute into rounded swellings separated by narrow constrictions. Without the inner membrane and cristae, this resistance disappears, allowing uniform elongation.

From DNA reorganisation to mitochondrial division

Pearling serves a vital biological function to coordinate the rearrangement of the mitochondrion’s contents. Mitochondria carry their own DNA, packaged into structures called nucleoids. As pearls form, nearby nucleoids actively moved into the expanding beads and become concentrated there, ensuring proper genetic distribution. Simultaneously, the narrow constrictions between the beads become potential sites of mitochondrial division. DRP1, a protein that acts as molecular “scissors” to help sever mitochondria, accumulates precisely at these narrow tethers while remaining absent from the beads. Mitochondria with more pearls had more potential division sites, leading to a higher frequency of clean division events. With continued pulling, a long mitochondrion can eventually be divided into several shorter mitochondrion fragments.

Professor Duan said: “The inner mitochondrial membrane is usually discussed mainly in terms of energy production, while its mechanical role receives much less attention. What we found is that it is the part that decides whether a stretched mitochondrion can pearl at all. Pearling is more than just a change in appearance. It reorganises mitochondrial DNA while simultaneously creating several potential division sites. By coordinating the distribution of genetic material with mitochondrial fission, this process may help cells maintain a healthy and functional population of mitochondria when subjected to mechanical stress.”

International collaboration and global impact

The study was co-first-authored by Wasi Iqbal of CUHK and Ben Zucker of Tel Aviv University. Professor Duan Liting and Professor Michael M. Kozlov were the corresponding authors. The research team also included CUHK researchers Liu Xiaoying, Wang Ruiru, Zhu Hongfei, Professor Chen Sijie and Professor Zhou Renjie, as well as Professor Liu Xingguo from the Guangzhou Institutes of Biomedicine and Health. This underscores CUHK’s key role as an international hub bridging global scientific excellence with Greater Bay Area innovation.