The Interface of Metabolism and Metabolic Regulation

Abstract

Metabolism is a complex process which not only breaks down nutrients into energy and biosynthetic precursors, but also synthesizes vital molecules that are necessary for life. Dysregulation of metabolism often results in diseases.

For example, diseases can be caused by dysregulation of rare metabolites, such as oncometabolite 2-hydroxyglutarate (2HG), which acts as a histone and DNA demethylase inhibitor. High levels of R-2HG are produced by mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) in brain cancer and acute myeloid leukemia, and S-2HG has been found to accumulate in renal cell carcinoma. We found that human phosphoglycerate dehydrogenase (PHGDH), a serine biosynthetic enzyme frequently amplified in breast cancer, produces R-2HG. However, the role of 2HG in normal physiology is largely unknown. We found a markedly high level of S-2HG in normal mouse testis, produced by testis-specific enzyme lactate dehydrogenase C (LDHC), which possibly regulates male fertility. These findings provide examples in which the moonlighting activity of a metabolic enzyme has a potentially important role in epigenetic regulation.

In addition to the regulatory role of metabolism, metabolic response to stress is also critical to cell survival. For example, autophagy degrades and recycles proteins and organelles essential for quality control and survival in starvation. We demonstrated that in starvation, autophagy deficiency attenuated mitochondrial function, resulting in reduced mitochondrial oxygen consumption and increased reactive oxygen species (ROS). We also found that an autophagy-deficient tumor derived cell line (TDCL) degrades nucleotide monophosphates to maintain energy charge for cellular function, which results in nucleotide deprivation and potentially cell death. These findings shine light on how autophagy maintains mitochondrial function in cancer cells and why autophagy is critical for their survival in starvation: to prevent energy crisis and fatal nucleotide pool depletion in starvation.

Metabolism and metabolic response not only regulates cellular functions, but can be largely determined by environment. Huge differences exist between cultured cells and tissue/tumor in vivo. For example, glutamine is the major carbon source of TCA cycle in cultured cells, but glucose provides most TCA cycle carbon in mouse tissues in vivo. Here we show preliminary data demonstrating that oxidative pentose phosphate pathway (oxPPP) flux is irreversible and represents only a small fraction of glucose uptake flux in cultured TDCLs, but in mouse lung or lung tumor, this pathway is either extremely reversible or accounts for a significant amount of glucose uptake.

Metabolism plays a fundamental role in biology, and it is also context dependent. Our findings on the diverse mechanisms that cells use to adapt metabolically in both pathological and physiological states provide new perspectives to understand metabolism and metabolic control.