The Study On Metabolic Regulation Mechanism Of Mitochondrial Phosphatase PTPMT1 To Mesenchymal Stem Cells

Background and aim: Mitochondria are highly dynamic organelles that play multiple important roles in cells.Protein tyrosine phosphatase mitochondrial 1(PTPMT1),a newly identified PTEN-like protein tyrosine phosphatase,is exclusively localized to the inner membrane of mitochondria,and widely expressed in various tissues.Disruption of PTPMT1 expression severely interferes with the function of mitochondrial,leading to a serious disease.Mesenchymal stem cell(MSC)is multipotent stem cell,which has clonal self-renewal and multilineage differentiation potential.Given the innate ability of these cells to promote hematopoiesis recovery and tissue repair,there is rising interest in utilizing MSC in a broad repertoire of cell based therapies for the treatment of diseases.However,the regulation and coordination of mitochondrial metabolism with MSC proliferation and differentiation is not fully understood.Here,we focus on the mechanism how mitochondrial energy metabolism is regulated and how mitochondrial bioenergetics and substrate utilization cooperatively coordinate both MSC self-renewal and differentiation.Methods: we created both Ptpmt1 null and conditional(floxed)alleles by gene targeting and generated Ptpmt1-deficient animal and cell models.We determined the effects of PTPMT1 depletion on MSC by analyzing cell proliferation,apoptosis,differentiation,cell cycle,energy metabolism and cell signaling.Results: Global disruption of PTPMT1 resulted in developmental arrest and postimplantation lethality.Deletion of PTPMT1 in hematopoietic-cell-specific knockout mice resulted in the stem cell pool drastically expanded.Deletion of PTPMT1 in MSC decreased proliferation and essentially blocked the adipocyte differentiation.This was accompanied by upregulation of cyclin-dependent kinase inhibitors and a significant cell cycle delay.Further analysis demonstrated that oxygen consumption of Ptpmt1-depleted cells was decreased,while glycolysis was concomitantly enhanced.In addition,under stress condition,compared to WT MSC,the aerobic metabolism of pyruvate in PTPMT1 knockout MSC decreased while the amino acid and fatty acid metabolism increased.Conclusion: This study established a crucial role of PTPMT1 in embryogenesis of mice and metabolic regulation of stem cell function.As a mitochondrial metabolic stressactivated checkpoint,PTPMT1 controlls MSC self-renewal and differentiation by metabolic regulation.