A new study published in Science Advances on March 7, 2025, may have uncovered a key piece of the puzzle behind ALS (Amyotrophic Lateral Sclerosis) and Frontotemporal Dementia (FTD)—two devastating neurological diseases that gradually strip away movement, cognition, and personality. The research, led by Yu Nie, Kornélia Szebényi, Lea M. D. Wenger, András Lakatos, and Patrick F. Chinnery, points to an unexpected player in the disease process: mitochondria, the tiny power plants of our cells.
By analyzing lab-grown brain models, researchers found a buildup of harmful mutations in mitochondrial DNA (mtDNA), particularly in astroglia—the brain’s support cells. This mitochondrial dysfunction may explain why certain areas of the brain are more vulnerable in ALS and FTD, and it could open new doors for treatment.
Why Do Some Brain Cells Die While Others Survive?
One of the biggest mysteries in ALS and FTD is why only certain brain regions deteriorate, despite the fact that the genetic mutations driving these diseases are present in every cell. If every neuron is exposed to the same genetic defect, why don’t they all suffer equally?
The study offers a possible answer: some brain cells, particularly astroglia, accumulate mitochondrial DNA mutations at higher rates, making them more vulnerable to dysfunction. When astroglia fail, the neurons they support are left defenseless—leading to the gradual degeneration seen in ALS and FTD.
How the Study Worked
To investigate, the researchers used human-induced pluripotent stem cells (hiPSCs)—a technology that allows scientists to take skin or blood cells and turn them into brain cells in the lab. They then used these cells to grow miniature 3D brain models, called cerebral organoids, mimicking real human brain tissue.
The organoids were developed from three groups:
- Patients with ALS-FTD carrying the C9ORF72 mutation (the most common genetic cause of these diseases)
- Genetically corrected versions of the same cells, where the mutation had been removed
- Healthy individuals with no disease-related mutations
By performing single-cell mitochondrial DNA sequencing, the team uncovered striking differences in mitochondrial health between cell types and disease states.
Key Findings
- Astroglia, not neurons, had the highest burden of mitochondrial DNA mutations in ALS-FTD models.
- Many of these mutations were de novo, meaning they arose spontaneously during development rather than being inherited.
- Some mutations escaped the body’s natural quality control systems, allowing them to build up to levels that could disrupt energy production in the brain.
- This mitochondrial dysfunction may set the stage for early cellular damage, long before symptoms appear.
Why This Matters
Most research on ALS and FTD has focused on neurons—the cells that control movement, memory, and cognition. But this study suggests that neuronal death may be a secondary consequence of something happening earlier: astroglial failure.
Astroglia play a critical role in maintaining a healthy brain environment, providing nutrients, removing waste, and regulating brain activity. If their mitochondria are failing due to unchecked mutations, they may be unable to support neurons properly, leading to progressive brain cell death.
A New Approach to Treatment?
These findings could reshape how we think about treating ALS and FTD. Instead of focusing solely on rescuing neurons after they start dying, researchers could explore ways to:
- Detect and eliminate harmful mitochondrial DNA mutations before they reach dangerous levels.
- Boost mitochondrial health in vulnerable cells like astroglia, preventing them from failing in the first place.
- Use gene-editing techniques to correct or remove damaging mutations.
If mitochondrial dysfunction is a root cause of ALS and FTD, therapies targeting mitochondrial health could slow or even prevent disease progression.
The Bigger Picture: Could This Apply to Other Brain Diseases?
While this research focuses on ALS and FTD, the implications could extend to other neurodegenerative disorders like Alzheimer’s and Parkinson’s.
Mitochondrial dysfunction has long been suspected in these diseases, but this study provides new evidence that specific brain cells are more vulnerable than others due to accumulated mtDNA mutations.
If future research confirms similar patterns in Alzheimer’s, Parkinson’s, or other conditions, mitochondrial-targeted therapies could revolutionize how we treat neurodegeneration as a whole.
Final Thoughts
For decades, scientists have been searching for the missing link in ALS and FTD. This study provides strong evidence that mitochondrial dysfunction in astroglia may be a crucial factor, potentially reshaping how we diagnose and treat these diseases.
The next challenge is clear: Can we intervene early enough to prevent neurodegeneration before it begins? If mitochondria truly hold the key to ALS and FTD, then the future of treatment may lie in preserving the brain’s support cells, not just saving neurons after they’re lost.
As researchers build on these findings, one thing is certain—this discovery could change the way we think about brain diseases forever.
Disclaimer:
This article is for informational purposes only and does not constitute medical or scientific advice. While the research discussed is based on a peer-reviewed study, scientific understanding evolves over time. Readers should consult medical professionals or scientific literature for the most current information regarding ALS, frontotemporal dementia, and mitochondrial research. The views expressed in this article do not necessarily reflect those of any specific institution or research body.
