Metabolic remodeling in bioenergetic disorders and cancer

Abstract

Human tissues differ by the type and the amount of energy substrate that they use and store, as dictated by their genetically programmed “metabolic rigidity” which defines the expression of tissue-specific catabolic and anabolic enzymes. For instance, adipocytes and neurons cannot perform fat oxidation, while cardiomyocytes utilize mainly fatty acids for ATP synthesis. These programs evolve during embryogenesis, with a typical burst of oxidative metabolism at birth. Bioenergetic homeostasis is regulated at the cellular level by effectors such as insulin and at the organismal level by the metabolic coupling between “energy donor” tissues, as the adipose tissue and the liver, and “receivers” and the muscle and the brain. In contrast to normal tissues, most tumors develop a dramatic “metabolic flexibility,” which allows them to consume whatever energy substrate is available. Yet, recent findings suggest that this flexibility is restricted by specific anabolic needs, so that alternative energy-transducing pathways are not selected randomly. Cancer cells also avoid the metabolic control by insulin, growth factors, and energy substrate starvation or excess by typical mutations in the MAPK, PI3K, RAS, and related pathways. Metabolic flexibility is made possible by the molecular rewiring of several metabolic pathways, which undergo branching, truncation, and reversal, as extensively documented for the Krebs cycle in the last decade. Like normal tissues, tumors can take advantage of metabolic coupling with other tissues, although this phenomenon remains poorly described. A related bioenergetic peculiarity of cancer cells concerns the metabolic coupling which occurs inside the tumors, between hypoxic-glycolytic and oxygenated-oxidative cancer cells. Undoubtedly, the fundamental studies on metabolic rigidity in normal tissues and on metabolic flexibility in cancer cells have revealed novel means of bioenergetic control, such as the essential signaling activity of the oncometabolites succinate, fumarate, oxoglutarate, or acetyl-CoA on HIF1α and NRF2 transcription factors, but also histone acetylases, respectively. The well-known regulation of OXPHOS by citrate, NADH, F1,6BP, Ca2+, and ATP on glycolytic enzymes IDH, PDH, and CIV also operates in cancer cells. Besides energy homeostasis, the study of cancer cell metabolic remodeling has shed light on the close links between the modalities of energy transduction and the capacity to synthesize amino acids or lipids necessary for tumor growth. Metabolic remodeling is not restricted to cancer and has been investigated in genetically inherited metabolic disorders as mitochondrial diseases or in the multifactorial metabolic syndrome. The results demonstrated the existence of alternative pathways of ATP synthesis and the effect of oxidative stress on TCA truncation via aconitase cleavage. Nowadays, large-scale analyses of comprehensive proteomics, transcriptomics, and metabolomics, potentially supported by computer modeling of metabolism and genetic approaches of subpathways validation, allow the deciphering of the fine changes in cell metabolism, both in physiology and pathology. Patterns of metabolic deviations and the corresponding genetic signatures can be confirmed by flux analyses using 13C-labeled isotopes of relevant metabolites. Analysis of deviant metabolism can identify potential targets so that therapeutic strategies could be derived from this knowledge, and ongoing preclinical studies aim to alter the alternative metabolic pathways in cancer.