Abstract
Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim)44 was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim44 functions as a membrane anchor of mtHsp70 to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. The process is dependent on inner membrane potential (Delta psi) and ATP hydrolysis on ATPase domain of mtHsp70. Here, we show that the gene delivery of Tim44 using pcDNA3.1 vector (pcDNA3.1/TIM44) into the balloon injury model of STZ-induced diabetic rats ameliorated neointimal proliferation. ROS production, inflammatory responses, and cell proliferation in injured carotid artery were diminished by delivery of pcDNA3.1/TIM44. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim44 normalized high-glucose-induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. Transfection of siRNA and pcDNA3.1/TIM44 using HASMC culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44. Tim44 and its related molecules in mitochondrial import machinery complex are novel targets in the therapeutic interventions for diabetes and its vascular complications.
Highlights
Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications
Transfection of siRNA and pcDNA3.1/TIM44 using human aortic smooth muscle cells (HASMCs) culture clarified that import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase was facilitated by Tim44
It becomes clear that hydrophobic as well as hydrophilic preproteins use a common translocase in the outer mitochondrial membranes, TOM complex, while there are two distinct translocase of inner mitochondrial membrane (TIM) complexes, TIM23 and TIM22 complexes, which are
Summary
Hyperglycemia induces the production of reactive oxygen species (ROS) from mitochondria, which is closely related to diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane (Tim) was identified by upregulation in streptozotocin (STZ)-induced diabetic mouse kidneys; Tim functions as a membrane anchor of mtHsp to TIM23 complex and is involved in the import of preproteins with mitochondria-targeted presequence into mitochondrial matrix. In vitro experiments using human aortic smooth muscle cells (HASMCs) revealed that the gene delivery of Tim normalized high-glucose–induced enhanced ROS production and increased ATP production, alterations in inner membrane potential, and cell proliferation. High glucose activates the membrane-bound NADPH oxidase pathway, generating O2.Ϫ, and is operational in endothelial cells, smooth muscle cells, and mesangial cells, while hyperglycemia leads to reduction in antioxidative defense, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [7,8] Another major site for the ROS production is mitochondria [9,10]. The functional analysis in yeast mitochondria clearly revealed that all three components of the import motor are essential for mitochondria matrix proteins with target sequence
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