Disruption of Mitochondrial‐associated ER membranes by HIV‐1 tat protein contributes to premature brain aging. (23rd November 2022)

• Record Type: Journal Article
• Authors: Arjona, Sterling P.; Allen, Charles N. S.; Santerre, Maryline; Gross, Scott; Soboloff, Jonathan; Booze, Rosemarie; Sawaya, Bassel E.
• Is Part Of: CNS neuroscience & therapeutics. Volume 29:Number 1(2023)
• Page Start: 365
• Page End: 377
• Publication Date: 2022-11-23
• Subjects: aging -- HIV‐1‐tat -- MAM‐tethering -- memory impairment -- mitochondria‐associated ER membranes -- PTPIP51 -- VAPB; Neuropharmacology -- Periodicals; Central nervous system -- Diseases -- Effect of drugs on -- Periodicals; 612.8
• DOI: 10.1111/cns.14011
• Languages: English
• ISSNs: 1755-5930

Abstract

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. Abstract : Schematic illustrating the effect of Tat on MAMs in neurons. Tat affects the interaction between MAM tethering proteins IP3R and VDAC, Bap31 and Fis1, Bap31 and Tomm40, and PTPIP51 and VDAC. The affected MAM tethering leads to dysregulated calcium transfer between the ER and mitochondria and increased ROS. Tat also affects PTPIP51 phosphorylation and thus its localization to MAMs. Kinase inhibitors gefitinib, dasatinib, and Rp‐cAMPs together can block PTPIP51 tyrosine phosphorylation even in the presence of Tat and can lead to PTPIP51 and VAPB interactions.