Stress-inducible WASF3 regulates brain metabolism and cognitive function

Wiskott-Aldrich syndrome protein family member 3 (WASF3) disrupts mitochondrial respiration and is induced in association with endoplasmic reticulum stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Because cognitive impairment is a hallmark of ME/CFS, we investigated the role of WASF3 in brain metabolism and function using WASF3 transgenic and knockout mouse models. WASF3 disrupted respiratory complex IV and localized to mitochondria-associated membranes, known to modulate cellular processes important for neuronal activity. Overexpression of WASF3 in the hippocampus, a critical region for memory formation, induced a metabolic shift toward glycolysis and promoted a "hypometabolic" state. Increased WASF3 also caused a reduction in ATPIF1, previously shown to facilitate cognitive function, and impaired learning. Conversely, WASF3 deficiency increased ATPIF1 level, enhanced oxidative metabolism, and preserved cognitive function under stress. Together, these findings demonstrate that WASF3 suppresses oxidative metabolism in the brain and contributes to cognitive dysfunction, providing mechanistic insights into the "brain fog" reported in ME/CFS.