Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: mechanistic insight into arterial tortuosity syndrome

Abstract

Mutations in glucose transporter 10 (GLUT10) alter angiogenesis and cause arterial tortuosity syndrome (ATS); however, the mechanisms by which these mutations cause disease remain unclear. It has been reported that in most cells, mitochondria are the major source of reactive oxygen species (ROS). Moreover, mitochondria are known to incorporate as well as recycle vitamin C, which plays a critical role in redox homeostasis, although the molecular mechanism(s) underlying mitochondrial vitamin C uptake are poorly understood. We report here that GLUT10 localizes predominantly to the mitochondria of smooth muscle cells and insulin-stimulated adipocytes, where GLUT10 is highly expressed. We further demonstrate that GLUT10 facilitates transport of l-dehydroascorbic acid (DHA), the oxidized form of vitamin C, into mitochondria, and also increases cellular uptake of DHA, which in turn protects cells against oxidative stress. This protection is compromised when GLUT10 expression in mitochondria is inhibited. In addition, we found that aortic smooth muscle cells from GLUT10-mutant mice have higher ROS levels than those from wild-type mice. Our results identify the physiological role of GLUT10 as the mitochondrial DHA transporter, and demonstrate that GLUT10 protects cells from oxidative injury. Furthermore, our findings provide a mechanism to explain the ascorbate in mitochondria and show how loss-of-function GLUT10 mutations may lead to arterial abnormalities in ATS. These results also reinforce the importance of vitamin C and ROS in degenerative diseases.

U937 cell apoptosis induced by arsenite is prevented by low concentrations of mitochondrial ascorbic acid with hardly any effect mediated by the cytosolic fraction of the vitamin

“…AA is directly taken up by the cells via sodium-AA cotransporters (SVCT1 and 2) [35][36][37] or, in alternative, under conditions associated with its extracellular oxidation, taken up as dehydroascorbic acid (DHA) by facilitative hexose transport. Most importantly, cytosolic vitamin C may then be transported in mitochondria as DHA [38][39][40] or, as recently demonstrated in our [41] and other [42] laboratories, directly as AA.…”

Glucose transporter type 10—lacking in arterial tortuosity syndrome—facilitates dehydroascorbic acid transport

“…The second theory suggests that GLUT10 is involved in the transport of dehydroascorbic acid (DAA), the oxidized form of the potent antioxidant ascorbic acid (AA) across the mitochondrial membranes, where GLUT10 has been localized with immunofluorescence studies in smooth muscle cells and adipocytes [10]. Upon being transported into mitochondrial matrix, DAA is reduced to AA, which can eliminate reactive oxygen species (ROS), thereby protecting the cell from oxidative stress.…”

Arterial Tortuosity Syndrome in a Neonate

“…Recessive lossoffunction mutations of the SLC2A10 gene lead to disinhibition of the transforming growth factor beta signaling pathway and inhibition of proper extracellular matrix formation causing compromised vascular integrity and disorganized con nective tissues 2,9) . Expression of the SLC2A10 gene has been identified in several tissues, and high levels of SLC2A10 gene expression have been noted in the aortic vascular smooth mus cle cells 9,10) . In this study, DNA sequencing genetic …”