Bidirectional relationship between mitochondrial dysfunction and dysregulated lipid metabolism in Multiple Sclerosis:...

Multiple Sclerosis (MS) is a heterogeneous neuroinflammatory disease with complex aetiology and diverse clinical presentations, often accompanied by neurodegenerative pathology. While current therapies primarily focus on immunomodulation, emerging evidence underscores a critical bidirectional interplay between mitochondrial dysfunction and lipid dysregulation in driving MS progression. Understanding this metabolic-mitochondrial axis may reveal novel therapeutic opportunities beyond immune modulation.

This scoping review systematically maps recent literature (2015-2025) to delineate the mechanistic connections between mitochondrial dysfunction and lipid dysregulation in MS, identify current knowledge gaps, and highlight translational opportunities for targeted intervention.

A systematic search of PubMed, Embase, and Scopus was conducted in 2025 following PRISMA-ScR guidelines. Thirty-six eligible studies examining mitochondrial-lipid interactions in human MS and preclinical models were included and synthesised thematically.

Evidence converges on a self-reinforcing pathological cycle in MS, where dysregulated lipid metabolism impairs mitochondrial integrity, amplifying reactive oxygen species generation, energy failure, and further lipid disruption. This cascade contributes to oligodendrocyte injury, demyelination, ferroptosis, and axonal degeneration. Importantly, therapeutic strategies that restore lipid-mitochondrial homeostasis, such as mitochondrial antioxidants, lipid modulators, and metabolically active immunotherapies, demonstrate promising neuroprotective effects in preclinical studies.

The evidence supports a model in which the bidirectional feedback loop between mitochondrial dysfunction and lipid dysregulation represents a significant mechanism contributing to neurodegeneration in MS. Clinically, these insights highlight opportunities for earlier diagnosis and more personalised disease management through the integration of lipid-based biomarkers into patient monitoring and treatment selection. Targeting this metabolic axis holds significant promise for developing next-generation disease-modifying therapies to slow disease progression, enhance neuroprotection, and improve functional recovery across different MS subtypes.