Mitochondrial secrets revealed: UCLA-led team discovers physics of how cell’s powerhouse splits to reproduce

Nearly every cell in your body depends on mitochondria to survive and function properly. Mitochondria earned the nickname "powerhouse of the cell" because they provide 90% of our bodies' energy. Less well-known are their roles in cellular signaling and in eliminating defective cells, which is important for stopping cancer before it starts.

As tiny, sausage-shaped mitochondria squirm around inside cells, they split off pieces through a process called fission, and combine with each other, also known as fusion, to keep up with the cell's complex energy demands. Too much fission leads to many undersized mitochondria; too much fusion leads to many oversized ones. Imbalances between fission and fusion are associated with serious disorders of the heart, lungs and brain as well as cancer and diabetes.

Chances to fight disease by correcting these kinds of imbalances have been stalled because the mechanisms of mitochondrial fission were a mystery. But now, humankind may be closer to solving that mystery thanks to an international research collaboration among bioengineers, physicists, biomedical engineers and biochemists led by the California NanoSystems Institute at UCLA, or CNSI. In a pair of recent studies published as back-to-back articles in the Journal of the American Chemical Society, the team shared their new discovery detailing how mitochondria split, setting up the potential for new treatments.

According to the researchers, mitochondria split in a two-stage process. They found that in each phase, the same protein is used in a different way.

"If we understand the main protein machinery regulating fission, maybe we can understand what's happening when that machinery doesn't work properly," said Haleh Alimohamadi, a UCLA postdoctoral researcher and first author of one study. "In specific diseases, seeing how mutations block fission could lead to new personalized treatments."

Interruptions in mitochondrial fission are connected to some of the most pervasive, deadly or debilitating health conditions: cardiovascular diseases, cancer, diabetes, Parkinson's disease, Alzheimer's disease, ALS and developmental defects. The new discovery could offer leads for addressing these conditions and more.

"We know that if this ability of mitochondria to change length is disrupted in some way, then you get all kinds of disease states," said CNSI member Gerard Wong, a corresponding author of both studies and a professor of bioengineering in the UCLA Samueli School of Engineering. "At the same time, we're only scratching the surface when it comes to mitochondrial fission and human health. There are likely connections to viral infections and all the diseases of aging."

The researchers used machine learning, experiments with genetic engineering and advanced X-ray imaging, and computer models of molecular interactions. What they found melds together two leading models for explaining the mechanics of mitochondrial fission.

First, proteins from what scientists refer to as the dynamin superfamily join up to spiral around the mitochondrion like a scaffold and squeeze its elastic membrane to form a narrow neck. This process is in line with a model suggesting fission is driven by the constriction of dynamin proteins. However, constriction by itself has never been experimentally observed to induce fission.

What happens next is in line with the competing, almost opposite model, which holds that fission is driven not by the assembly (and squeezing) but rather the disassembly of the spiral scaffold into free-floating dynamin protein. The research team showed that, indeed, the floating dynamin proteins drive fission, but only when the mitochondria have been pre-squeezed into a narrow tube first. The individual free-floating proteins then flip around and use their own shape to bend the membrane inward even further by pressing against it.

In fact, at the threshold for fission, something unexpected happens: The membrane buckles suddenly and becomes so narrow that the mitochondrion can no longer remain in one piece. This snap-through instability, studied in physics and mechanical engineering, finalizes fission in a manner like an umbrella abruptly turned inside out by a wind gust.

"The biggest thing we found in these two sister papers is that it's not only assembly by itself but also disassembly that unleashes the hidden power of the dynamin protein," said Elizabeth Luo, a UCLA doctoral student and first author of one study. "The key is that the same protein is recharged by hydrolysis after completing its first role, so the cell doesn't need a new protein to complete the final step."

The team also made a direct connection between defects in fission and disease. They focused on a specific mutation to the gene that encodes dynamin protein. In this case, a single substitution in the alphabet that makes up DNA is known to cause potentially deadly problems with the development of the brain. The researchers showed that this mutation interferes with fission in mitochondria.

Beyond the discoveries about mitochondria, this research may offer clues into the mechanisms behind other important cellular behaviors. For instance, the process by which a cell takes in a substance from the outside - vital for both communication between cells and the delivery of medicine - employs a similar change in the membrane. The process, called endocytosis, is dependent on dynamin.

"In a way, nature is quite frugal," said Wong, who is also a professor of chemistry and biochemistry and of microbiology, immunology and molecular genetics at UCLA. "The same conceptual themes keep showing up. These mechanisms we put together for mitochondria may wind up playing a part in endocytosis, which is one of the most fundamental and important functions in a cell."

Alimohamadi begins her appointment as an assistant professor of molecular biology and biochemistry at UC Irvine this fall, where she will follow up to explore mechanisms of assembly and disassembly in other biological contexts.

Blake Hill of the Medical College of Wisconsin is co-corresponding author of the study led by Luo. Wong, Alimohamadi, Luo and Hill are co-authors of both studies, along with Kelsey Nolden of the Medical College of Wisconsin and Liting Duan of the Chinese University of Hong Kong. The study led by Alimohamadi was co-authored by Rena Yang of UCLA; Xiaoying Liu and Wasi Iqbal of the Chinese University of Hong Kong; and Shivam Gupta and Taraknath Mandal of the Indian Institute of Technology Kanpur. Michelle Lee of UCLA was a co-author of the study led by Luo.

Both studies received support from the National Science Foundation and the National Institutes of Health. The study led by Alimohamadi received support from the American Heart Association, India's Science and Engineering Research Board and the U.S. Department of Energy. The study led by Luo received support from Taiwan's Ministry of Education and a UCLA Dissertation Year Fellowship.