Redox and structural regulation of Protein Tyrosine Phosphatase Mitochondrial 1 (PTPMT1)

• Grant number: 23/02968-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2023
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Luciana Elena de Souza Fraga Machado
• Grantee: Luca Paulino Otvos
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/02605-3 - Structural and functional characterization of mitochondrial protein phosphatases by redox metabolism and their role in cell biology, AP.JP

Abstract

PTPMT1 is a mitochondrial protein tyrosine phosphatase and is involved in ATP synthesis and insulin secretion in pancreatic beta cells and in cardiolipin biosynthesis. PTPMT1 was the first protein phosphatase identified in mitochondria. Although PTPMT1 has been described as a PLIP (PTEN like protein), because it has a sequence in the PTP loop similar to that of PTEN, and because it has a high affinity for the substrate phosphatidylinositol-5-phosphate (PI(5)P) in vitro, the PTEN activity has not been confirmed in vivo. Important studies have demonstrated the role of PTPMT1 in the synthesis of cardiolipin through the dephosphorylation of phosphatidylglycerolphosphate, leading to the formation of phosphatidylglycerol. Thus, PTPMT1 deficiency causes changes in mitochondrial morphology and mitochondrial respiratory capacity. Another important role of PTPMT1 is its activity in pancreatic beta cells, in which its inhibition leads to increased insulin secretion. Thus, some works have identified possible inhibitors for PTPMT1, as an important target for the treatment of type 2 diabetes. It is known that cytoplasmic protein tyrosine phosphatases are inhibited by oxidation. Considering that the mitochondria represents one of the most important sites of production of cellular oxidants, and that these can cause S-thiol modifications of PTPMT1, we postulate that PTPMT1 can be inhibited by oxidation, making it an important target for the treatment of diabetes.