Exploring the Role of Mitochondrial DNA in CD4+ T Cells for Multiple Sclerosis Progression

Multiple Sclerosis (MS) is a complex immune-mediated neurodegenerative disease affecting the central nervous system (CNS) with an unclear origin. CD4+ T cells, crucial players in the immune system, have shown mitochondrial dysfunction in MS patients, potentially driving the disease’s neurodegenerative process. Mitochondrial DNA (mtDNA) variants could theoretically influence MS activity and progression, making it essential to explore their role in MS pathology.

A recent study examined mtDNA in CD4+ T cells of MS patients, analyzing both cross-sectional and longitudinal data. By sequencing the mtDNA of these cells, the researchers aimed to assess differences in mtDNA between MS patients and healthy controls (HCs) and over time in MS patients.

Methods and Cohort
The study included 61 patients with Clinically Isolated Syndrome (CIS) or Relapsing-Remitting MS (RRMS) who were matched with HCs by age and sex. The cohort was part of the Berlin CIS Cohort and included clinical assessments such as disability scales, MRI scans, and optical coherence tomography at two key points: six months (VIS1) and 36 months (VIS2) after disease onset.

To gather data, the researchers enriched CD4+ T cells from blood samples, then isolated mtDNA for whole genome sequencing, achieving high-quality data for analysis. They evaluated several variables, including total variants, deleterious mutations, and specific regions of the mitochondrial genome.

Findings
The study found that mitochondrial genotype in CD4+ T cells did not significantly vary between MS patients and HCs or across different time points for MS patients. Key findings included:
Total Variant Comparison: The number of mtDNA variants was similar between MS patients and HCs. Furthermore, the distribution of these variants was consistent over time for MS patients.

Deleterious Variants: The deleterious burden of mtDNA mutations, primarily in Complex I and Complex IV regions, was similar across groups. These findings aligned with prior studies linking complex-specific mitochondrial dysfunction to MS but did not indicate an mtDNA genotype association.

Haplogroup Influence: Certain mitochondrial haplogroups (such as J and T) exhibited higher deleterious burdens, but the distribution of these haplogroups was independent of MS presence.

Longitudinal Stability: Over time, persistent and transient mutations in mtDNA remained stable, with few fluctuations in their frequency or deleterious impact.

No Disease Progression Link: Despite prior evidence that CD4+ T cells in MS have impaired mitochondrial function, this study found no significant association between mtDNA variants in these cells and MS progression.

Discussion
These results suggest that while mitochondrial dysfunction in CD4+ T cells is a feature of MS, it may not stem directly from specific mtDNA mutations. This aligns with previous studies where mtDNA differences alone were insufficient to explain MS progression. Environmental factors, nuclear DNA, or other cellular mechanisms could modulate mitochondrial function and, consequently, MS disease course.

This study’s findings have implications for therapeutic strategies focusing on mitochondrial function in MS, suggesting that treatments targeting mitochondrial health rather than specific mtDNA mutations might be more promising.

Conclusion
This comprehensive study highlights that mitochondrial genotype alone does not appear to influence MS progression. It underscores the need for further research into the environmental and genetic factors influencing mitochondrial function in MS, opening pathways for future treatments targeting cellular bioenergetics rather than mtDNA-specific alterations.

Reference:
Cortes-Figueiredo, F., Asseyer, S., Chien, C. et al. CD4+ T cell mitochondrial genotype in Multiple Sclerosis: a cross-sectional and longitudinal analysis. Sci Rep 14, 7507 (2024).