Number of mitochondrial DNA copies tied to disease progression
Study links fewer copies to more advanced MS
As multiple sclerosis (MS) progresses, the disease may reduce the number of mitochondrial DNA copies, suggesting the number of copies could serve as a biomarker for disease progression and response to treatment.
That’s according to a genetic study involving data from thousands of patients of European ancestry.
Mitochondria are small organelles within cells that generate the majority of the energy required for cellular function. They contain their own DNA, and the number of copies of this mitochondrial DNA (mtDNA) can serve as an indicator of mitochondrial health. Researchers have proposed mtDNA copy number as a potential biomarker for MS and other neurodegenerative diseases.
“However, further research is needed to confirm [mtDNA copy number] as a reliable biomarker and a deeper understanding of the molecular mechanisms is necessary to develop targeted therapeutic interventions,” the researchers wrote.
The study, “Mitochondrial DNA Copy Number as a Hidden Player in the Progression of Multiple Sclerosis: A Bidirectional Two-Sample Mendelian Randomization Study,” was published in Molecular Neurobiology.
Tracking disease progression
MS occurs when nerve cells in the brain and spinal cord become inflamed and damaged, leading to a range of MS symptoms. In MS, chronic inflammation is believed to disrupt normal mitochondrial function, potentially causing the organelles to rupture and release their DNA into the surrounding cellular environment.
Research suggests that changes in mitochondria begin early in the course of MS and interfere with how nerve cells produce and use energy, further contributing to neurodegeneration. Therapeutic interventions, such as stem cell therapy, may bring mitochondrial DNA to near-normal levels.
It’s not clear if changes in mitochondria worsen MS symptoms, or if disease progression reduces the number of mitochondrial DNA copies. To clarify this, the researchers turned to Mendelian randomization, a method that uses people’s genetic differences to help understand whether one thing actually causes another, instead of just being linked to it.
The researchers drew on genetic information from 383,476 people of European ancestry whose data are available publicly from the U.K. Biobank. They looked at variations in the genetic code, known as single-nucleotide polymorphisms (SNPs), with a known function in the number of mitochondrial DNA copies.
To look for SNPs linked to the severity of MS — measured using the Expanded Disability Status Scale (EDSS) — the researchers also collected genetic information from 12,584 patients of European ancestry registered with the International Multiple Sclerosis Genetics Consortium.
A first analysis, which checked whether mitochondrial DNA copy number caused MS to worsen based on the presence of those SNPs, revealed no clear link between the two. This means that changes in the number of mitochondrial DNA copies does not appear to drive progression of the disease.
However, when the researchers looked at the relationship the other way around — whether MS affects the number of mitochondrial DNA copies — they found a causal relationship, which they said provides “evidence that MS progression leads to a reduction in [mitochondrial DNA copy number].”
The researchers checked their results for consistency and to make sure other genetic factors weren’t interfering, a problem called pleiotropy. They found no signs of such a problem, and the results stayed the same.
“This study highlights the potential link between mitochondrial dysfunction and the progression of MS, particularly through [mitochondrial DNA copy number],” the researchers wrote. “Integrating tissue-specific analyses can enhance our understanding of mitochondrial contributions to MS progression and may provide more precise biomarkers for monitoring disease severity and therapeutic response.”
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