Mitochondria and Multiple Sclerosis Progression: What mtDNA Copy Number Reveals
Multiple sclerosis (MS) is classically understood as an immune-mediated disease of the central nervous system, but this article shifts attention toward a less visible biological layer: mitochondrial dysfunction. The study, titled “Mitochondrial DNA Copy Number as a Hidden Player in the Progression of Multiple Sclerosis,” asks whether mitochondrial DNA copy number (mtDNA-CN) is simply associated with MS progression or whether it may sit within a causal pathway. MS progression involves chronic neuroinflammation, demyelination, axonal injury, and gradual neurological disability, particularly in secondary progressive and primary progressive disease forms. The authors focus on mtDNA-CN because mitochondria are central to ATP production, oxidative stress regulation, apoptosis, and neuronal bioenergetics—processes deeply relevant to neurodegeneration.
Why mtDNA-CN Matters Biologically
Mitochondrial DNA copy number reflects, at least indirectly, mitochondrial content and mitochondrial genomic stability. In neurons and immune cells, altered mtDNA-CN may indicate impaired oxidative phosphorylation, reduced respiratory capacity, or compensatory mitochondrial biogenesis. The article notes that mtDNA is more vulnerable than nuclear DNA because it lacks protective histones and has less efficient repair mechanisms; damage in key mitochondrial regions such as the D-loop can disturb replication and reduce mtDNA-CN. In MS, chronic inflammation, reactive oxygen species, glutamate excitotoxicity, and cytokine-driven metabolic stress may progressively damage mitochondria, linking mitochondrial decline to axonal failure and irreversible disability.
Why the Authors Used Mendelian Randomization
A major problem in previous mtDNA-CN and MS studies is directionality: does low mtDNA-CN contribute to MS progression, or does progressive MS reduce mtDNA-CN? Observational studies cannot easily resolve this because they are vulnerable to confounding and reverse causation. To address that issue, the authors used bidirectional two-sample Mendelian randomization (MR), a genetic epidemiology method that uses single-nucleotide polymorphisms as instrumental variables. The diagram on page 3 outlines two workflows: one testing mtDNA-CN as the exposure and MS progression as the outcome, and the other testing MS progression as the exposure and mtDNA-CN as the outcome. The MR assumptions shown in the page 4 diagram are relevance, independence from confounders, and exclusion restriction.
Study Design, GWAS Sources, and Instruments
The study combined large genome-wide association study datasets from European-ancestry populations. For mtDNA-CN, the authors used UK Biobank data from 383,476 European participants, with mtDNA-CN estimated using the AutoMitoC pipeline. For MS progression, they used International Multiple Sclerosis Genetics Consortium data from 12,584 European-ancestry MS cases, where neurological disability was assessed using EDSS and transformed into the age-related MS severity score to account for age-related disability differences. Genetic instruments were selected using genome-wide or suggestive thresholds, linkage disequilibrium clumping, harmonization of alleles, exclusion of problematic palindromic SNPs, and F-statistic filtering to reduce weak-instrument bias.
The Key Finding: MS Progression Appears to Reduce mtDNA-CN
The forward MR analysis found no statistically significant evidence that genetically predicted mtDNA-CN causes MS progression. After outlier filtering, 43 SNPs were used as instruments, and the IVW result was non-significant, with no evidence of heterogeneity or horizontal pleiotropy. In contrast, the reverse MR analysis suggested that MS progression causally reduces mtDNA-CN: using 76 SNPs, the IVW estimate was β = −0.010, 95% CI −0.019 to −0.001, P = 0.036. This result was also supported by several robust MR methods, including penalized IVW, robust IVW, RAPS, MR-cML, debiased IVW, and MR-Lasso. The forest plots on pages 5 and 7 visually summarize this asymmetry: the forward direction is null, whereas the reverse direction consistently trends negative.
Mechanistic Interpretation and Biomarker Potential
The most biologically plausible interpretation is not that low mtDNA-CN initiates MS progression, but that progressive MS imposes metabolic and inflammatory stress that gradually erodes mitochondrial integrity. The authors describe a pathway in which demyelination increases ion-channel redistribution and Na+/K+-ATPase demand, raising ATP requirements; inflammation and oxidative stress then impair mitochondrial function, contributing to ATP failure, calcium dysregulation, apoptosis, Wallerian degeneration, and permanent neurological impairment. Clinically, mtDNA-CN may therefore be more useful as a progression-associated biomarker than as a primary causal driver. The article also argues that mtDNA-CN could complement neurofilament light chain, a marker of neuroaxonal injury, and GFAP, a marker of astroglial activation, to provide a more multidimensional view of MS pathology.
Limitations and Future Directions
The study is methodologically strong because it uses bidirectional MR, multiple sensitivity analyses, pleiotropy tests, outlier detection, and MR Steiger directionality testing, but its conclusions still require caution. The GWAS datasets were primarily European, limiting generalizability to other ancestries; the MS progression instruments used a relaxed P-value threshold, which may increase weak-instrument or pleiotropy concerns despite mitigation strategies; and MR cannot fully replace mechanistic experiments. Future studies should validate the findings in diverse populations, integrate tissue-specific mtDNA-CN measures from blood, cerebrospinal fluid, and CNS tissue, and test whether mtDNA-CN improves prediction when combined with NfL, GFAP, MRI markers, and clinical progression scores. Overall, the article supports a refined model: mitochondrial dysfunction is deeply involved in MS progression, but mtDNA-CN may be more a molecular footprint of disease progression than an upstream genetic cause.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Sabaie, H., Taghavi Rad, A., Shabestari, M. et al. Mitochondrial DNA Copy Number as a Hidden Player in the Progression of Multiple Sclerosis: A Bidirectional Two-Sample Mendelian Randomization Study. Mol Neurobiol 62, 11643–11653 (2025). https://doi.org/10.1007/s12035-025-04980-9
