Mitochondrial DNA Copy Number and Multiple Sclerosis Progression: A Hidden Signal of Neurodegeneration
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system, characterized by immune-mediated demyelination, axonal injury, and progressive neurological disability. While immune dysregulation remains central to MS pathogenesis, increasing attention has been directed toward mitochondrial dysfunction as a contributor to neurodegeneration. The article examines mitochondrial DNA copy number (mtDNA-CN), a quantitative indicator of mitochondrial genomic content, as a possible factor in MS progression. Because mitochondria regulate oxidative phosphorylation, ATP production, apoptosis, and oxidative stress responses, changes in mtDNA-CN may reflect cellular attempts to compensate for metabolic stress or, conversely, mitochondrial failure during disease progression.
Why mtDNA-CN Matters as a Biomarker
Mitochondrial DNA is particularly vulnerable to oxidative and inflammatory damage because it lacks protective histones and has less efficient repair mechanisms than nuclear DNA. In MS, chronic inflammation, microglial activation, reactive oxygen species, and excitotoxic injury may all impose sustained mitochondrial stress. The article emphasizes that previous observational studies reported inconsistent associations between mtDNA-CN and MS severity, partly because cross-sectional and case–control designs cannot reliably distinguish cause from consequence. This uncertainty makes mtDNA-CN scientifically important: it may either contribute to disease progression or serve as a downstream marker of accumulated neurodegenerative damage.
Study Design: Bidirectional Mendelian Randomization
To address causality, the authors used a bidirectional two-sample Mendelian randomization approach. Mendelian randomization uses genetic variants as instrumental variables to infer causal relationships while reducing confounding and reverse causation. In the forward analysis, mtDNA-CN was treated as the exposure and MS progression as the outcome. In the reverse analysis, MS progression was treated as the exposure and mtDNA-CN as the outcome. The study drew mtDNA-CN genetic instruments from 383,476 European ancestry participants in the UK Biobank and MS severity data from 12,584 European ancestry MS cases in the International Multiple Sclerosis Genetics Consortium. MS progression was assessed through age-related MS severity scores derived from disability measures such as the Expanded Disability Status Scale.
Principal Finding: MS Progression May Reduce mtDNA-CN
The most important result was asymmetric. The forward analysis found no statistically significant evidence that genetically predicted mtDNA-CN causes MS progression. In contrast, the reverse analysis suggested that MS progression may causally reduce mtDNA-CN. Using the inverse variance weighted method, the authors reported a negative association between MS progression and mtDNA-CN, with β = −0.010, 95% CI = −0.019 to −0.001, and P = 0.036. Several robust Mendelian randomization methods, including penalized IVW, robust IVW, RAPS, MR-cML, debiased IVW, and MR-Lasso, supported the same negative direction of effect. This finding suggests that mitochondrial genomic depletion may be more likely to arise as a consequence of advancing MS pathology rather than serving as an initiating causal factor.
Biological Interpretation: Energy Failure and Neurodegeneration
The biological interpretation is consistent with current models of progressive MS. Chronic demyelination increases axonal energy demand, partly because demyelinated axons require redistribution of ion channels and greater Na⁺/K⁺-ATPase activity to maintain conduction. At the same time, inflammation and oxidative stress impair mitochondrial function and oxidative phosphorylation. As mitochondrial performance declines, ATP production becomes insufficient, ionic homeostasis deteriorates, calcium accumulates, and apoptotic or degenerative cascades may be activated. The observed reduction in mtDNA-CN may therefore represent a molecular footprint of progressive mitochondrial exhaustion in MS. Rather than being merely a passive marker, reduced mtDNA-CN could reflect a critical stage in the transition from inflammatory injury to irreversible neuroaxonal degeneration.
Strengths and Limitations of the Evidence
A major strength of the study is its use of bidirectional Mendelian randomization, which directly addresses the directionality problem that has limited earlier observational research. The authors also applied extensive sensitivity analyses, including heterogeneity testing, MR-Egger intercept analysis, MR-PRESSO, RadialMR, leave-one-out analyses, and MR Steiger directionality testing. These analyses found no substantial evidence of heterogeneity or horizontal pleiotropy, supporting the robustness of the main result. Nevertheless, the study has limitations. The datasets were primarily derived from individuals of European ancestry, limiting generalizability to other populations. In addition, the reverse analysis used a relaxed genetic instrument threshold for MS progression, which can increase statistical power but may also raise concerns about weak instruments or pleiotropy, despite the authors’ corrective analyses.
Clinical and Research Implications
This article positions mtDNA-CN as a promising but not yet definitive biomarker of MS progression. Its value may be greatest when integrated with other biomarkers, such as neurofilament light chain for neuroaxonal injury and glial fibrillary acidic protein for astroglial activation. The study also highlights the importance of tissue context: mtDNA-CN measured in peripheral blood may reflect systemic inflammation and immune-cell mitochondrial status, whereas cerebrospinal fluid or brain tissue measurements may better capture central nervous system mitochondrial injury. Future studies should validate these findings in larger and more diverse populations, investigate tissue-specific mtDNA-CN dynamics, and experimentally define the mechanisms linking progressive MS pathology to mitochondrial genomic depletion. Overall, the work strengthens the concept that mitochondrial dysfunction is not peripheral to MS biology but may be deeply embedded in the mechanisms of irreversible neurological decline.
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
