Mitochondrial Calcium Sensor Tusc2 Protects the Aging Hippocampus from Proteostasis Collapse in a Sex-Specific Manner

Progressive mitochondrial dysfunction coupled with calcium dyshomeostasis is a hallmark of aging and neurodegenerative conditions, yet the molecular links to cognitive decline remain unclear. Moreover, although sex differences in susceptibility to neurodegeneration are well recognized, their molecular basis remains poorly defined. In our previously engineered mouse model, systemic depletion of Tusc2 (Fus1), a mitochondrial calcium-regulatory protein, accelerates aging and recapitulates key features of human aging, including sex-specific cognitive decline. Here, we identify Tusc2 as a key modulator of hippocampal (HP) resilience to aging. To define the impact of Tusc2 loss on molecular determinants of cognition, we profiled HP transcriptomes in both sexes and proteomes in males at 4 months of age, when sex-specific differences in cognitive behavior first emerge. Male knockout HP exhibited broad mitochondrial dysfunction, including suppression of oxidative phosphorylation (OxPhos) proteins, activation of the ATF4 branch of the integrated stress response (ISR), and coordinated downregulation of translational, proteasomal, and synaptic pathways. These molecular alterations were accompanied by increased protein aggregate size, consistent with impaired proteostatic capacity, and reduced PSD-95 neuropil intensity, indicative of compromised synaptic integrity in the HP. In contrast, female knockout HP exhibited comparatively modest transcriptional alterations and preferential activation of adaptive ATF6-associated unfolded protein response (UPR) pathways, consistent with a protective response that may be influenced by estrogen signaling, sex chromosome complement, epigenetic regulation, and other sex-dependent mechanisms. Comparative analysis with aging human HP datasets revealed significant and broad overlaps, suggesting that Tusc2 deficiency recapitulates key molecular features of human brain aging. Together, these findings identify TUSC2 as a principal regulator of mitochondrial calcium homeostasis that contributes to maintenance of proteostatic and synaptic integrity of the HP during aging, and reveal marked sex differences in mitochondrial stress resilience. These results establish Tusc2 deficiency as a mechanistically defined model for investigating early, potentially reversible stages of mitochondrial and proteostatic decline in brain aging.