Decoding multiple sclerosis: linking autoimmunity, and nutrition/environmental factors to mitochondrial dysfunction...

Multiple sclerosis (MS) is a chronic neurodegenerative and inflammatory disorder of the central nervous system (CNS) characterized by focal demyelinated lesions and axonal loss. Disease onset is initiated by an autoimmune cascade wherein autoreactive T and B lymphocytes target self-antigens on oligodendrocytes and the myelin sheath. This inflammatory environment, compounded by subsequent oxidative stress, drives progressive demyelination and axonal degeneration. Ultimately, this pathology culminates in a neurodegenerative phase that underlies both the characteristic episodic relapses and the irreversible clinical progression observed in MS patients. Beyond genetic predisposition, environmental and lifestyle factors significantly influence MS incidence and progression; these prominently include vitamin D deficiency, gut microbiota dysbiosis, obesity, smoking, and Epstein-Barr virus (EBV) infection. At the cellular level, mitochondria are indispensable for maintaining neuronal homeostasis within the CNS, yet they exhibit extreme vulnerability to neuroinflammatory insults. A growing body of evidence underscores mitochondrial dysfunction as a core driver of MS pathogenesis, directly implicating organelle defects in axonal degeneration, chronic inflammation, and demyelination processes that collectively dictate long-term neurological disability. Intriguingly, MS-induced mitochondrial impairment appears to be partially driven by aberrant autophagy cascades. Because the pharmacological inhibition of autophagy has been shown to significantly alleviate behavioral symptoms in experimental autoimmune models, modulating this pathway represents a crucial pathophysiological axis. Consequently, safeguarding mitochondrial fitnessand targeting its interplay with nutritional and environmental factors via natural bioactive compounds holds substantial therapeutic promise. This review highlights the pivotal role of mitochondrial dysfunction in MS progression and examines novel therapeutic strategies, with a specific focus on modulating autophagy to restore mitochondrial homeostasis.

The online version contains supplementary material available at 10.1007/s13205-026-05018-0.