Farris, T.; González-Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment. Int. J. Mol. Sci.2024, 25, 7406.
Farris, T.; González-Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment. Int. J. Mol. Sci. 2024, 25, 7406.
Farris, T.; González-Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment. Int. J. Mol. Sci.2024, 25, 7406.
Farris, T.; González-Ochoa, S.; Mohammed, M.; Rajakaruna, H.; Tonello, J.; Kanagasabai, T.; Korolkova, O.; Shimamoto, A.; Ivanova, A.; Shanker, A. Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment. Int. J. Mol. Sci. 2024, 25, 7406.
Abstract
Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression 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-/- brain, suggesting a weakened 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, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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