Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome.

Observed Findings

• Nitric oxide-mediated nitrosylation of cysteine residues is a reversible signaling mechanism regulated by antioxidant enzyme systems.
• Chronic oxidative and nitrosative stress can inactivate denitrosylation and transnitrosylation enzymes, creating a pathologic 'hypernitrosylated' state.
• Hypernitrosylation impairs electron transport chain enzymes and mitochondrial function.
• Hypernitrosylation alters protein conformation, triggering loss of immune tolerance and autoimmune responses against nitrosylated self-proteins.
• Bacterial translocation may serve as a driving mechanism for hypernitrosylation and autoimmune activation in ME/CFS.

Inferred Conclusions

• Chronic nitrosative stress leading to hypernitrosylation may be a unifying mechanism explaining symptom heterogeneity in ME/CFS, including fatigue, cognitive impairment, and immune dysfunction.
• Disruption of antioxidant systems via nitrosylation represents a potential amplification loop in ME/CFS pathophysiology.
• Autoimmune responses directed against nitrosylated proteins may perpetuate ME/CFS pathology independent of initial triggering events.
• Increased intestinal permeability and bacterial translocation could be an upstream driver of hypernitrosylation in ME/CFS.

Remaining Questions