Structural support protein takes center stage in maintaining mitochondria

Some brain disorders are straightforward, such as the direct frontal lobe assault of a concussion or traumatic brain injury. Others, like Alexander disease, are akin to guerilla warfare.

Patients suffering from this genetic disorder experience erosion in the function of astrocytes, cells that support neurons in a variety of ways. Like a city under siege, the brain and its neurons eventually deteriorate along with their astrocyte infrastructure.

Alexander disease is caused by mutations in the gene housing the instructions for the glial fibrillary acidic protein (GFAP). This ropelike protein is known as an intermediate filament, one of the structural components that gives shape and structure to a cell and all its constituent parts.

“Ever since learning about this disorder, I have found myself asking two simple questions,” said Su-Chun Zhang, MD, PhD, the Jeanne and Gary Herberger Leadership Chair in Neuroscience and the director of and professor in the Center for Neurologic Diseases at Sanford Burnham Prebys Medical Discovery Institute.

“What does GFAP do in astrocytes? And why do GFAP mutations cause Alexander disease?”

Zhang and an international team of collaborators published findings November 26, 2025, in the Proceedings of the National Academy of Science demonstrating GFAP’s involvement in maintaining the mitochondria serving as the power plants of our cells. The researchers also show how the GFAP mutations responsible for Alexander disease disrupt the delicate balance of mitochondria splitting and merging to meet the cells’ energy needs.  

Mitochondria are as dynamic as a dance troupe, joining together in a process known as fusion and splitting apart in what is called fission. This complex choreography allows the ramping up or slowing down of energy production when the cell demands more or less fuel. Prior research indicated that there may be a link between GFAP and mitochondrial function, but what connected the two remained a mystery.

In the new study, the scientists began by investigating the location of GFAP within the cell, and how those coordinates matched up with mitochondria.

“When we look at the spatial relationship between mitochondria and GFAP in astrocytes, it's very striking,” said Zhang. “GFAP fibers are wrapped around almost every mitochondrion.”

The research team then used gene editing to deactivate the GFAP gene in a group of astrocytes and compared them with normal astrocytes. They observed a dramatic drop in the number of mitochondria in astrocytes lacking GFAP.

“Without GFAP, the mitochondria fuse together in a very long chain,” said Zhang. “It is almost like there is only one mitochondrion in a cell.

“That finding confirmed our hypothesis about the relationship, so then we had to figure out how it works.”

The scientists conducted an experiment showing that GFAP promotes mitochondrial fission rather than blocking fusion. They demonstrated that it is likely that GFAP fibers encourage fission by serving as an anchor for a protein called dynamin-related protein 1 (Drp1) known to be essential to the process of splitting mitochondria.

“We found that wherever GFAP fibers come into contact with mitochondria, you also will find Drp1 in that exact location,” said Zhang. “And then you observe mitochondrial division.”

The research team discovered that GFAP fibers kick off the splitting of mitochondria by wrapping around the organelles and applying a constricting force. The fibers then serve as a scaffold for the attachment of Drp1. These proteins subsequently form a spiral that narrows to divide a mitochondrion into two pieces. The whole process would be like a butcher using twine to mark where a sausage needs to be cut and then wrapping around and tightening a wire at that spot to complete the job.

“We showed that GFAP is more than just a biomarker for astrocytes; it actually does something,” said Zhang. “It's not this simple cytoskeletal protein that only holds organelles together, but rather an active participant in the division of mitochondria.”

The researchers connected their observations back to Alexander disease by demonstrating that disease-causing GFAP mutations force cells to make an overabundance of GFAP fibers, which leads to too much mitochondrial fission in astrocytes.

“This has significant implications for understanding the pathogenesis of Alexander disease as well as the development of therapies for this devastating disorder,” said Zhang.

Going forward, Zhang plans to broaden the team’s GFAP studies beyond the context of Alexander disease.

“GFAP upregulation in astrocytes actually happens in all neurological and psychiatric diseases,” said Zhang.

“We want to know why this occurs, and we think that GFAP has potential as a biomarker for many brain disorders.”

Ding Xiong, PhD, research fellow at Duke-National University of Singapore (NUS) Medical School, is first author of the study.

Additional authors include:

• Fang Yuan, research fellow at Sanford Burnham Prebys
• Linghai Kong, senior research and development scientist at BrainXell
• Ye Sing Tan from Duke-NUS Medical School
• Zijun Sun, Xueyan Li, Emily Abella and Albee Messing from the University of Wisconsin-Madison

The study was supported by the National Institutes of Health, Singapore Ministry of Health, Singapore Ministry of Education, Natural Science Foundation of China, Sichuan Science and Technology Program and Duke-NUS Medical School.

The study’s DOI is 10.1073/pnas.2524111122.