An image shows thousands of mitochondria (purple dots) surrounding nuclei of about 50 human kidney cells. (Gwangbeom Heo/Stanford University)
Stanford News - May 21st, 2025 - by Glennda Chui
Mitochondria are the cell’s power plants: They turn the food we eat into the energy our cells can use. But when stress hijacks the process they use to maintain their quality, they get snipped into useless fragments and go into a tailspin that spreads from cell to cell and triggers a wide range of human diseases. As researchers learn more about the health impacts of rogue mitochondria, they’ve been searching for ways to prevent or treat them.
Now, researchers at the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University say they’ve found a way to protect mitochondria from stress induced by exposure to a highly reactive molecule called hydrogen peroxide. This particular type of damage is linked to neurogenerative diseases like Parkinson’s and Amyotrophic Lateral Sclerosis (ALS), heart disease, diabetes, inflammatory bowel disease, and cancer, among others.
In experiments with human kidney cells, the research team reported, adding a small molecule called SP11 to the fragmented mitochondria made them hale and whole again.
The team described their work in a May 6 report in Nature Communications, and Stanford has patented SP11 as a potential candidate for drug development.
“If we can keep mitochondria in pristine shape, we may really help address many chronic human diseases. That’s why we embarked on this project,” said Stanford Professor Daria Mochly-Rosen, a senior author of the report whose research into the chemistry of proteins has yielded both potential and successfully deployed drugs.
Not just a power plant
Although mitochondria are best known for producing energy, that’s not their only role. “They’re so busy! This organelle is so critical,” Mochly-Rosen said. For instance, they’re responsible for constructing some of the cell’s molecular building blocks and for deliberately killing cells whose DNA is damaged.
For a long time, scientists assumed that mitochondria were confined to their host cells, but they recently discovered this isn’t true. “Now we know they can exit one cell and enter another one,” Mochly-Rosen said. “When bad mitochondria do this to a healthy cell, they can kill it. When healthy mitochondria do it to a sick cell, they can help it heal.”
Seventeen years ago, Mochly-Rosen and her colleagues trained a microscope on cells from a rat with high blood pressure and discovered that the mitochondria were fragmented into small pieces. This set off a quest to find out what was happening and how to prevent or fix it.
SLAC and Stanford researchers found a small molecule called SP11 that prevents damage to mitochondria (purple) – the cell’s power plants – caused by exposure to oxidating chemicals. It has potential for treating mitochondria-associated ailments like ALS, heart disease and diabetes, in which oxidating chemicals are formed in the body. Healthy mitochondria (left) split and unite all the time as a way to exchange components that are required to maintain their quality. Adding an oxidizing agent like hydrogen peroxide (center) kept mitochondria from dividing into equal halves and snipped them into useless fragments instead. The addition of SP11 (right) made the mitochondria healthy and whole again. | Gwangbeom Heo / Stanford University
Hijacking fission
Mitochondria are often depicted as little jellybeans whose shape never changes, said Suman Pokhrel, who was a PhD student at SLAC and Stanford at the time he led the study. But in real life, they form an ever-changing, fibril-like network. Thousands of them surround the nucleus of each cell, and they’re constantly dividing and fusing with each other. Mitochondria need to maintain a balance between division and fusion to stay healthy, increase their numbers, and make enough energy.
In healthy mitochondria, a protein called Drp1 attaches to the mitochondrial membrane and initiates division via a go-between protein called Mff. But when mitochondria send out distress signals – for instance, if they’ve been attacked by a reactive oxygen molecule like hydrogen peroxide and can’t repair the damage fast enough – Drp1 attaches to a protein called Fis1 and uses it as a go-between instead.
Fis1 directs mitochondrial fission in yeast, but in humans, it only brings grief. It hijacks the normal process mitochondria use to divide neatly in half and instead squeezes them into uneven pieces that fragment into even smaller ones that don’t produce enough energy.
Top: A protein called Drp1 (blue) prompts the cell’s power plants, mitochondria (tan), to divide. Drp1 normally acts through a go-between protein called Mff (green). Bottom: But when exposure to oxidizing chemicals stresses mitochondria, another go-between protein, Fis1 (pink) hijacks the division process, squeezing mitochondria into unequal parts. Those parts fracture into smaller and smaller fragments until they can’t produce enough energy to keep the cell healthy. The damage spreads from cell to cell and causes a variety of human ailments, including Parkinson’s and heart disease. | Pokhrel et al., Nature, 6 May 2025
One obvious solution would be to block Drp1 from coupling with Fis1, Pokhrel said. But incapacitating Drp1 was out of the question because cells need it for other things, including normal cell division. And the surface of the Fis1 molecule doesn’t have any obvious pocket where a drug could dock. As Pokhrel puts it, “Both are essentially undruggable.”
But maybe, he thought, Fis1 molecules that have been activated into their mitochondria-chopping state would have a place where a drug molecule could plug in to prevent or reverse the damage.
A well-hidden Achilles heel
Finding this weak spot and a potential drug to target it required more than three years of work that Pokhrel performed with Mochly-Rosen and SLAC/Stanford Professor Soichi Wakatsuki as his PhD advisers, along with colleagues from Stanford, SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL), and Meiji University in Japan.
Through repeated rounds of computer simulations, biochemical experiments, X-ray crystallography and scattering at SSRL, and other techniques, the team learned how Fis1 changes shape in response to oxidative stress.
“The stress response process of Fis1 has turned out to be pretty complex,” Wakatsuki said, “and untangling it required tour-de-force multidisciplinary efforts.”
