Recharging Brain Cells Could Be The Next Step Against Multiple Sclerosis

Researchers have discovered that damage to the brain cells’ “powerhouses,” called mitochondria, may be behind coordination and movement problems in people with multiple sclerosis. This damage particularly affects the cerebellum, the region of the brain responsible for balance and motor control. The study suggests that protecting mitochondria could be a new way to treat the symptoms of the disease.

Multiple sclerosis (MS) is a chronic neurological disease in which the immune system attacks the brain and spinal cord, affecting communication between the brain and the body. One of the areas most often affected is the cerebellum, a region of the brain responsible for motor functions such as balance, coordination, and fine control of movement.

Many patients with multiple sclerosis, especially in the more advanced stages of the disease, experience tremors, difficulty walking, and loss of coordination. Although it is known that there is damage to this area of ​​the brain, the exact mechanisms behind it were not yet fully understood.

This study, carried out by researchers at the School of Medicine at the University of California Riverside, USA, investigated in more depth what is happening in the cerebellum of people with multiple sclerosis, both in examinations of human tissue after death and in mice that develop a similar form of the disease, called EAE (experimental autoimmune encephalomyelitis).

The research team analyzed postmortem cerebellar tissue from patients with secondary progressive multiple sclerosis, along with samples from healthy individuals obtained from the NeuroBioBank of the National Institutes of Health and the Cleveland Clinic.

The researchers found that a key factor appears to be dysfunction of mitochondria, tiny structures within cells that function as cellular “powerhouses.” When these mitochondria malfunction, brain cells, especially the so-called Purkinje cells (which are essential for motor control), begin to deteriorate.

In cerebellar tissue from patients with progressive multiple sclerosis, they observed a significant reduction in the activity of a specific part of the mitochondria called complex IV (COXIV), which is essential for energy production.

Purkinje cells are marked in red, green and yellow in the image.

In addition, these individuals had a significant loss of Purkinje cells and signs of demyelination (loss of the protective layer of nerves), inflammation and damage to nerve extensions, called axons.

When this same process was studied in mice with advanced experimental autoimmune encephalomyelitis, the results were similar: mitochondria were damaged, their cellular respiration was impaired, genes linked to energy production were less active and there was also a loss of Purkinje cells.

These similarities between humans with multiple sclerosis and mice with experimental autoimmune encephalomyelitis suggest that the animal model is quite useful for studying the disease. More importantly, the study reinforces that mitochondrial dysfunction may be directly involved in the degeneration of the cerebellum in multiple sclerosis.

This opens up new possibilities for treatments that aim to protect or restore mitochondrial function, which could help preserve motor function in MS patients and slow the progression of the disease.

In the future, the team will investigate whether the mitochondrial impairment found in Purkinje cells also affects other brain cells, such as oligodendrocytes, which help form white matter, or astrocytes, which support overall brain function.

“To answer this, one of our ongoing research projects focuses on studying mitochondria in specific types of brain cells in the cerebellum. This research could pave the way for finding ways to protect the brain early on, such as by increasing energy in brain cells, helping them repair their protective myelin sheath, or calming the immune system before excessive damage is done. This is especially important for people with MS who have difficulties with balance and coordination, as these symptoms are linked to damage to the cerebellum.” Tiwari-Woodruff, one of the authors, emphasized that research related to the disease is vital to improving lives.

Seema Tiwari-Woodruff (right) and one of her students Credit: University of California, Riverside

LEIA MAIS:

Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss

Kelley C. Atkinson, Shane Desfor, Micah Feri, Maria T. Sekyi, Marvellous Osunde, Sandhya Sriram, Saima Noori, Wendy Rincón, Britany Bello, and Seema K. Tiwari-Woodruff

PNAS. June 16, 2025. 122 (25) e2421806122

https://doi.org/10.1073/pnas.2421806122

Abstract: 

In multiple sclerosis (MS), cerebellar gray matter atrophy, white matter demyelination, and Purkinje cell (PC) loss have been linked to tremors, impaired motor control, and loss of coordination. Similar pathologies have been observed in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). This study hypothesized that inflammatory demyelination of the cerebellum alters overall mitochondrial function and is a contributor to axon degeneration and PC loss. Postmortem cerebellar tissue from MS patients, particularly those with secondary progressive MS, showed decreased mitochondrial complex IV (COXIV) activity and significant PC loss. Inflammation, PC axon demyelination, axon degeneration, and parallel fiber loss were also evident. These findings were mirrored in late-stage EAE mice, which also showed increased inflammation and demyelination, reduced PC COXIV activity, and overall PC loss. Further analysis of EAE mice revealed altered mitochondrial structure, modified mitochondrial respiration, and reduced levels of mitochondrial genes involved in energy production. These findings indicate that both human MS and mouse EAE share similar cerebellar changes linked to mitochondrial dysfunction. Thus, late-stage EAE is a valuable model for studying MS-related cerebellar pathology, and mitochondria may be a potential therapeutic target for MS treatment.