Non-glucose metabolism in cancer cells--is it all in the fat?

Cancer biologists seem to have overlooked tumor metabolism in their research endeavors over the last 80 years of the last century, only to have "rediscovered Warburg" (Warburg et al. 1930; Warburg, Science 123(3191):309-314, 1956) within the first decade of the twenty-first century, as well as to suggest the importance of other, non-glucose-dependent, metabolic pathways such as such as fatty acid de novo synthesis and catabolism (ß-oxidation) (Mashima et al., Br J Cancer 100:1369-1372, 2009) and glutamine catabolism (glutaminolysis) (DeBerardinis et al., Proc Nat Acad Sci 104(49):19345-19350, 2007). These non-glucose metabolic pathways seem to be just as important as the Warburg effect, if not potentially more so in human cancer. The purpose of this review is to highlight the importance of fatty acid metabolism in cancer cells and, where necessary, identify gaps in current knowledge and postulate hypothesis based upon findings in the cellular physiology of metabolic diseases and normal cells.

The Golden Freeway: a preliminary evaluation of a pilot study advancing information technology as a social intervention for boys with Duchenne muscular dystrophy and their families.

Established information technology was used in an attempt to reduce social isolation by providing each family who had a child with Duchenne muscular dystrophy with a personal computer, and e-mail and Internet connectivity. Seventy-four of the 88 families in the north of England (i.e. Cumbria, Durham, Northumberland, Teesside, and Tyne and Wear) with a boy with Duchenne muscular dystrophy who was diagnosed before January 2000 had the equipment installed. Evaluations of equipment usage and parental perceptions of the project were carried out at 3 and 12 months post-installation. Results from quantitative and qualitative interviews with parents indicated that benefits accrued to the families and to the boys themselves: family relationships can be extended, and the boys can acquire a degree of independence which, according to parents' views, can boost self-confidence and self-esteem. As hoped, social isolation was felt to have been reduced, and an occupation, interest and enjoyment provided. The greatest use of the computer was for schoolwork with siblings sharing in this. Cost proved to be a problem for a number of families. For the project team, there were unexpected aspects: creating an e-community was more difficult than anticipated, more training was required and not all families would ever use the equipment to its fullest. However, families did emphasise the value of the project as a way of opening the world for their sons.

Mitochondrial beta-oxidation.

Mitochondrial beta-oxidation is a complex pathway involving, in the case of saturated straight chain fatty acids of even carbon number, at least 16 proteins which are organized into two functional subdomains; one associated with the inner face of the inner mitochondrial membrane and the other in the matrix. Overall, the pathway is subject to intramitochondrial control at multiple sites. However, at least in the liver, carnitine palmitoyl transferase I exerts approximately 80% of control over pathway flux under normal conditions. Clearly, when one or more enzyme activities are attenuated because of a mutation, the major site of flux control will change.

Effects of feeding on albumin synthesis in hypoalbuminemic hemodialysis patients.

BACKGROUND: Hypoalbuminemia is a powerful predictor of morbidity and mortality in hemodialysis (HD) patients and results from a reduction in albumin synthesis. It is not known if this is associated with any impairment of the normal response to feeding. METHODS: Protein turnover and albumin synthesis were measured in the fasting and fed state using a primed constant infusion of L-[1-(13)C]leucine in seven hypoalbuminemic (albumin < or = 36 g/L) HD patients (HHD), seven normoalbuminemic (albumin > or = 40 g/L) HD patients (NHD) and nine age-matched normal controls. RESULTS: The increase in albumin synthesis on feeding was impaired in HHD patients (fasting 15.0 +/- 1.5 vs. fed 17.7 +/- 2.9%, P = NS) compared to NHD (fasting 13.7 +/- 0.9 vs. fed 17.4 +/- 1.0%, P < 0.05) and controls (fasting 12.9 +/- 0.6 vs. fed 15.2 +/- 0.6%, P < 0.05). In addition, body mass index and percent body fat were significantly (P < 0.05) lower in HHD (20.8 +/- 1.3 kg/m2, 23.4 +/- 2.0%) than NHD (26.7 +/- 1.3 kg/m2, 33.1 +/- 3.2%) or controls (26.2 +/- 1.1 kg/m2, 32.6 +/- 1.8%). There was no difference in dietary protein or energy intake in the three groups. CONCLUSIONS: There are differences of body composition and protein metabolism in HHD patients that may be related to an impaired metabolic response to feeding.

Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency.

Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding, and preliminary experiments suggested that the variant protein displayed prolonged association with chaperonins and delayed formation of active enzyme. Accordingly, the molecular pathogenesis of SCAD deficiency may rely on intramitochondrial protein quality control mechanisms, including degradation and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate with mitochondrial hsp60 chaperonins; however, the variant SCAD proteins remained associated with hsp60 for prolonged periods of time. Biogenesis experiments at two temperatures revealed that some of the variant proteins (R22W, G68C, W153R, and R359C) caused severe misfolding, whereas others (R147W, G185S, and Q341H) exhibited a less severe temperature-sensitive folding defect. Based on the magnitude of in vitro defects, these SCAD proteins are characterized as folding-defective variants and mild folding variants, respectively. Pulse-chase experiments demonstrated that the variant SCAD proteins either triggered proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.