Oncometabolism: A Paradigm for the Metabolic Remodeling of the Failing Heart

Abstract

Heart failure is associated with profound alterations in cardiac intermediary metabolism. One of the prevailing hypotheses is that metabolic remodeling leads to a mismatch between cardiac energy (ATP) production and demand, thereby impairing cardiac function. However, even after decades of research, the relevance of metabolic remodeling in the pathogenesis of heart failure has remained elusive. Here we propose that cardiac metabolic remodeling should be looked upon from more perspectives than the mere production of ATP needed for cardiac contraction and relaxation. Recently, advances in cancer research have revealed that the metabolic rewiring of cancer cells, often coined as oncometabolism, directly impacts cellular phenotype and function. Accordingly, it is well feasible that the rewiring of cardiac cellular metabolism during the development of heart failure serves similar functions. In this review, we reflect on the influence of principal metabolic pathways on cellular phenotype as originally described in cancer cells and discuss their potential relevance for cardiac pathogenesis. We discuss current knowledge of metabolism-driven phenotypical alterations in the different cell types of the heart and evaluate their impact on cardiac pathogenesis and therapy.

Keywords: Warburg effect; cardiac hypertrophy; cell signaling; energy metabolism; glycolysis.

Figure 1

Glycolysis provides important intermediates for anabolic processes. Glucose is transported into the cell via glucose transporters and first converted into glucose-6-phosphate by hexokinase (HK) and subsequently converted into fructose-6-phosphate. Alternatively, it acts as a substrate for the oxidative pentose phosphate pathway (oxPPP) to generate ribulose-5-phosphate, thereby also generating reducing equivalents in the form of NADPH. Fructose-6-phosphate is converted into fructose-1,6-phosphate by phosphofructokinase 1 (PFK-1) or it can be utilized in the non-oxidative pentose phosphate pathway (non-oxPPP), ultimately resulting in ribose-5-phosphate generation. Moreover, the hexosamine biosynthetic pathway (HBP) utilizes fructose-6-phosphate, together with glutamine, to generate glucosamine-6-phosphate (GlcN-6P) via glutamine:fructose-6-phosphate aminotransferase (GFAT). Subsequently, the end product UDP-N-acetylglucosamine (UDP-N-GlcNAc) is generated in a multi-step conversion. Glyceraldehyde-3-phosphate generated by aldolase (ALDO) and triose-phosphate isomerase (TPI) further undergoes glycolysis. After conversion into 1,3-BP-glycerate via glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), the glycolytic intermediate 3-P-glycerate is generated via phosphoglycerate kinase (PGK) and converted into pyruvate by pyruvate kinase (PK). It can also be used for the synthesis of amino acids. Pyruvate is either converted into lactate by lactate dehydrogenase (LDH), used to generate amino acids, or enters the mitochondria to fuel the TCA cycle.

Figure 2

HIF-1a signaling and regulation. Under normoxic conditions, prolyl hydroxylase enzymes (PHDs) hydroxylate HIF-1a and mark it for degradation by the von Hippel–Lindau E3 ubiquitin ligase (VHL). HIF-1a hydroxylation by PHDs requires alpha-ketoglutarate and oxygen as substrates and yields succinate and CO₂. PHD activity is suppressed under hypoxic conditions and following the accumulation of succinate. This prevents HIF-1a degradation and allows its translocation into the nucleus, where it dimerizes with HIF-1b and binds to HIF-responsive elements (HRE) in the promotor region of genes. This activates the expression of target genes involved in glucose metabolism, angiogenesis and cellular proliferation.

Figure 3

Schematic overview of glutamine metabolism. In the cytosol, glutamine is converted into alpha-ketoglutarate (α-KG) or transported into mitochondria. Within the mitochondria, glutamine is first converted into glutamate by glutaminase (GLS) and then to α-KG. Glutamate conversion into α-KG is facilitated by three enzymes: glutamate pyruvate transaminase (GPT), glutamate dehydrogenase (GLDH) and glutamate oxaloacetate transaminase (GOT). Subsequently, α-KG enters the TCA cycle and aids the generation of succinate, thereby replenishing the TCA cycle (anaplerosis). Alternatively, it can be used to generate citrate (reductive carboxylation) which can be transported to the cytosol. In the cytoplasm, isocitrate dehydrogenase (IDH-1) facilitates the conversion of α-KG into citrate. Citrate is utilized for acetyl-CoA and oxaloacetate generation by ATP-citrate lyase (ACLY). Cytosolic acetyl-CoA forms the substrate for lipogenesis and the acetylation of proteins.