{"doi":"10.3390/ijms25137406","title":"Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment","abstract":"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.","journal":"International Journal of Molecular Sciences","year":2024,"id":500529,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1318238,"name":"Salvador González Ochoa","orcid":"0000-0002-5787-4759","position":1,"is_corresponding":false},{"id":1218175,"name":"Muna Mohammed","orcid":"0000-0002-2129-6483","position":2,"is_corresponding":false},{"id":564146,"name":"Harshana Rajakaruna","orcid":null,"position":3,"is_corresponding":false},{"id":340986,"name":"Jane Tonello","orcid":null,"position":4,"is_corresponding":false},{"id":329326,"name":"Thanigaivelan Kanagasabai","orcid":"0000-0002-9867-8076","position":5,"is_corresponding":false},{"id":340629,"name":"Olga Y. Korolkova","orcid":null,"position":6,"is_corresponding":false},{"id":252938,"name":"Akiko Shimamoto","orcid":null,"position":7,"is_corresponding":false},{"id":340024,"name":"Alla V. Ivanova","orcid":"0000-0002-4149-5105","position":8,"is_corresponding":false},{"id":250501,"name":"Anil Shanker","orcid":"0000-0001-6372-3669","position":9,"is_corresponding":false},{"id":1318575,"name":"Tonie Farris","orcid":null,"position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":null,"created_at":"2026-07-19T02:10:08.435215Z","pmid":"39000512","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}