Mitochondrial measures in neuronally enriched extracellular vesicles predict brain and retinal atrophy in multiple sclerosis

Mitochondrial dysfunction plays an important role in multiple sclerosis (MS) disease progression. Plasma extracellular vesicles are a potential source of novel biomarkers in MS, and some of these are derived from mitochondria and contain functional mitochondrial components.To evaluate the relationship between levels of mitochondrial complex IV and V activity in neuronally enriched extracellular vesicles (NEVs) and brain and retinal atrophy as assessed using serial magnetic resonance imaging (MRI) and optical coherence tomography (OCT).Our cohort consisted of 48 people with MS. NEVs were immunocaptured from plasma and mitochondrial complex IV and V activity levels were measured. Subjects underwent OCT every 6 months and brain MRI annually. The associations between baseline mitochondrial complex IV and V activities and brain substructure and retinal thickness changes were estimated utilizing linear mixed-effects models.We found that higher mitochondrial complex IV activity and lower mitochondrial complex V activity levels were significantly associated with faster whole-brain volume atrophy. Similar results were found with other brain substructures and retinal layer atrophy.Our results suggest that mitochondrial measures in circulating NEVs could serve as potential biomarkers of disease progression and provide the rationale for larger follow-up longitudinal studies.