Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory...

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca²⁺ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2^-/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2^-/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4⁺ T cells and Granzyme-B in CD8⁺T cells. We also found fewer FOXP3⁺ T-regulatory cells and Ly49G⁺ NK and Ly49G⁺ NKT cells in female Tusc2^-/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2^-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca²⁺ dynamics. Overall, the data suggest that dysregulation of Ca²⁺-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2^-/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca²⁺- signaling pathways in the brain should be explored to improve cognitive health.