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Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging
Booze, Rosemarie
Booze, Rosemarie
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Journal article
Date
2022-11-23
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Committee member
Department
Cancer and Cellular Biology
Microbiology, Immunology and Inflammation
Medical Genetics and Molecular Biochemistry
Neural Sciences
Microbiology, Immunology and Inflammation
Medical Genetics and Molecular Biochemistry
Neural Sciences
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DOI
http://dx.doi.org/10.1111/cns.14011
Abstract
Introduction: Mitochondrial-associated ER membranes (MAMs) control many cellular functions, including calcium and lipid exchange, intracellular trafficking, and mitochondrial biogenesis. The disruption of these functions contributes to neurocognitive disorders, such as spatial memory impairment and premature brain aging. Using neuronal cells, we demonstrated that HIV-1 Tat protein deregulates the mitochondria. Methods & Results: To determine the mechanisms, we used a neuronal cell line and showed that Tat-induced changes in expression and interactions of both MAM-associated proteins and MAM tethering proteins. The addition of HIV-1 Tat protein alters expression levels of PTPIP51 and VAPB proteins in the MAM fraction but not the whole cell. Phosphorylation of PTPIP51 protein regulates its subcellular localization and function. We demonstrated that the Tat protein promotes PTPIP51 phosphorylation on tyrosine residues and prevents its binding to VAPB. Treatment of the cells with a kinase inhibitor restores the PTPIP51-VAPB interaction and overcomes the effect of Tat. Conclusion: These results suggest that Tat disrupts the MAM, through the induction of PTPIP51 phosphorylation, leading to ROS accumulation, mitochondrial stress, and altered movement. Hence, we concluded that interfering in the MAM-associated cellular pathways contributes to spatial memory impairment and premature brain aging often observed in HIV-1-infected patients.
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Citation
Arjona SP, Allen CNS, Santerre M, et al. Disruption of Mitochondrial-associated ER membranes by HIV-1 tat protein contributes to premature brain aging. CNS Neurosci Ther. 2023; 29: 365-377. doi: 10.1111/cns.14011
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CNS Neuroscience & Therapeutics, Vol. 29, Iss. 1
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