ATP is essential for maintaining the ionic balance of

ATP is essential for maintaining the ionic balance of the lens (Michael and Bron, 2011). Without sufficient ATP there is an ionic imbalance due to Na+K+ATPase dysfunction. Previous studies have shown that rabbit lenses incubated ex vivo without glucose rapidly lost ATP in their lens epithelium and fiber A 967079 mg (Winkler and Riley, 1991). In human patients, a deficiency of GLUT1 in erythrocytes leads to leakage of monovalent cations through the red blood cell membrane, resulting in osmotic instability and hemolysis (Bawazir et al., 2012) (Shibata et al., 2017). In the mouse lens epithelium, a decrease in GLUT1 led to a decrease in lactate and ATP production. The decrease in ATP would lead to disruption of the ionic balance of the lens due to water entry, causing cataracts similar to osmotic cataracts observed in previous studies (Auricchio and Libondi, 1983) (Bender, 1994). The use of SD-OCT proved to be a reliable and non-invasive method of investigating the longitudinal development of cataracts in mice. The SD-OCT images of the LensΔGlut1 lens mirrored what was noted on histological analysis. Only a small number of studies have used SD-OCT to image cataracts in humans (Ortiz et al., 2013) (Mansouri et al., 2014) and, to our knowledge, none have been conducted using mice. SD-OCT has many advantages over histology including the ability to conduct longitudinal studies on animals as well as the elimination of tissue artifacts from fixation and processing tissue sections. In summary, our studies provide new insight into the metabolism of the lens by using a genetic approach to delete Slc2a1 from the mouse lens. We showed that mature lens fiber cells are dependent on glycolysis to maintain their metabolic needs and structural integrity while lens epithelium and differentiating fiber cells can oxidize other substrates. Our results show that changes in expression levels of metabolic transporters can contribute to cataract formation.
Acknowledgements Supported by grants from the National Eye Institute (R01 EY012042, P30 EY025585, R01 EY024549, P30 EY012576), the National Heart Lung and Blood Institute (HL087947), the Department of Veterans Affairs (I01 BX002340, Research Career Scientist) and an unrestricted grant from Research to Prevent Blindness to Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
Introduction Cancer cells usually show different metabolic requirements than healthy cells to satisfy the higher demand aimed for proliferation. This evidence was first described by Otto Warburg in the 20's, and it is already considered as one of the hallmarks of cancer [1], [2]. Tumor cells usually increase their nutrients uptake, mainly glucose and glutamine. The increase in glycolytic flux, independent of oxygen concentration (i.e. “aerobic glycolysis”), is employed to obtain NADPH as well as the required precursors for biosynthesis [3]. Besides the promotion of cell proliferation, glucose metabolism protects from cell death. Thus, an increase in glycolytic flux turn cells into a more resistant phenotype to apoptosis [4]. The inhibition of cell metabolism by nutrient deprivation has been proposed as an effective approach to kill tumor cells [5]. After glucose withdrawal, reactive oxygen species (ROS) are generated by mitochondrial dysfunction [6], but sometimes cancer cells evolved to avoid this metabolic stress by mechanisms still unknown. Glucose uptake is higher in tumor cells by an increase in protein production and membrane translocation of facilitative glucose transporters (GLUTs). Glucose uptake in cancer cells has been mainly associated with GLUT1, which is overexpressed by growth factors and usually correlates with cancer malignancy [7]. However, it may also involve other GLUTs [8], [9], [10]. In addition to a drop in oxygen levels, the core of a growing tumor also displays glucose starvation [11], and nutrient removal alters expression or location of GLUT transporters. It has been described that at least one of the GLUT isoforms is upregulated in response to glucose deprivation in cancer cells [12]. Moreover, when non-tumor cells are under growth factors deprivation, GLUT1 is usually internalized and degraded in lysosomes. Consequently, glucose uptake and metabolism dramatically decrease before cell death. Cancer cells often overexpress GLUT1 in response to the absence of growth factors, maintaining glucose metabolism and becoming resistant to apoptosis [13].