GLUT10 maintains the integrity of major arteries through regulation of redox homeostasis and mitochondrial function

Abstract

Glucose transporter 10 (GLUT10) is a member of the GLUT family of membrane transporters, and mutations in this gene cause arterial tortuosity syndrome (ATS). However, the physiological role and regulation of GLUT10 in arteries remains unclear. To further understand its physiological roles in major arteries, we examined the regulatory mechanisms of GLUT10 in ASMCs and aortic tissues. Interestingly, we find that targeting of GLUT10 to mitochondria is increased in ASMCs under both stress and aging conditions, which enhances dehydroascorbic acid (DHA) uptake and maintains intracellular ascorbic acid (AA) levels. We further demonstrate that the targeting of GLUT10 to mitochondria is important to maintain redox homeostasis, mitochondrial structure and mitochondrial function in ASMCs. A missense mutation of GLUT10 (Glut10G128E) impairs mitochondrial targeting in ASMCs. Consequently, ASMCs isolated from Glut10G128E mice exhibit increased reactive oxygen species (ROS) levels, fragmented mitochondria and impaired mitochondrial function, as well as enhanced cell proliferation and migration. In vivo, mitochondrial structure is altered, and ROS levels are heightened in aortic tissues of Glut10G128E mice. Furthermore, increased number and disorganization of ASMCs, along with progressive arterial wall remodeling were observed in aortic tissues of Glut10G128E mice. These defects were coincident with elevated systolic blood pressure in aged Glut10G128E animals. Our results describe a novel mechanism that GLUT10 targeting to mitochondria under stress and aging condition has a critical role in maintaining AA levels, redox homeostasis and mitochondrial structure and function in ASMCs, which is likely to contribute to the maintenance of healthy vascular tissue.

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

“…Histopathology of ATS patient vascular tissue invariably shows substantial fragmentation of the elastic laminae in the tunica media [1] while conversely the previously described Glut10 G128E mouse model mainly presented with increased arterial wall thickness, most prominent at the age of 15 months [22,24]. Our model only reveals mild elastic fiber anomalies in all genotypes, that are likely age-related changes.…”

“…Vitamin C plays an essential role as an anti-oxidant and in collagen synthesis. Since recent evidence indicates that GLUT10 function may include transport of DHA into subcellular compartments [14,17,24], it could be hypothesized that murine developmental processes do not suffer from Slc2a10 mutations and localized vitamin C hypovitaminosis, which would explain the absence of a relevant phenotype in Slc2a10 mutant mice [16,23].…”

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

“…In artery cells, there is intracellular targeting of GLUT10 to mitochondria, where it functions in redox control through the accumulation of dehydro-ascorbate [ 24 ]. Consistent with a role of GLUT10 in compartmentalisation of ascorbate within arterial cells, mice with a GLUT10 G128E mutation exhibit increased levels of reactive oxygen species, fragmented mitochondria and cross-linking of proteins at the endoplasmic reticulum [ 203 ].…”

“…The function of DHA transport may lie in maintaining redox levels in cells (for example in human erythrocytes with high GLUT1 levels) or in subcellular compartments [ 178 ]. GLUT10 deficiency is associated with blood vessel damage [ 24 , 203 ], while a deficiency in GLUT14 transport of DHA is associated with inflammatory bowel disease [ 3 ]. A more complete study of all the GLUTs that transport DHA is necessary before ascorbate is considered the main substrate for any of the GLUT proteins.…”

Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training

“…This finding is consistent with studies performed in cardiac, smooth or skeletal muscle that investigated these GLUT isoforms in the regulation of muscle cell growth, development, and redox buffering. These studies demonstrated: (1) An ~150% increase in GLUT1 protein levels following pressure overload in the heart [154]; (2) a transient but ~900% increase in GLUT3 mRNA levels during L6 myocyte fusion [83]; (3) an ~45% increase in GLUT3 protein levels in L6 myotubes following long-term insulin-like growth factor-1 exposure [81]; and (4) an increase in oxidative stress following loss of function mutations in GLUT10 arterial smooth muscle cells [155,156]. Future studies in muscle-specific GLUT knockout mouse models are needed to fully assess the role of any of these GLUT isoforms in the regulation of resistance training-induced muscle glucose transport.…”