Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle

Abstract

Background Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands. Scope of review The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time. Major conclusions Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.

Metabolic management of microenvironment acidity in glioblastoma

“…A large part of the confusion on mitochondrial dysfunction in cancer comes from the incorrect assumption that oxygen consumption observed in cancer cells is linked to ATP synthesis through OxPhos ( 14 , 28 , 29 , 40 , 50 – 53 ). Many cancers, including GBM, can survive in hypoxia (0.1% oxygen) or in a solution of potassium cyanide, a Complex IV inhibitor, findings that would exclude normal OxPhos as a source of ATP synthesis ( 54 – 57 ).…”

Glucose fluxes in glycolytic and oxidative pathways detected in vivo by deuterium magnetic resonance spectroscopy reflect proliferation in mouse glioblastoma

“…Assessment of mitochondrial function in situ further suggested the coupling between basal respiration and energy production in both glioma cell lines. While this should be taken with caution considering glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway for ATP synthesis in several cancer cells, including CT2A ( Chinopoulos and Seyfried, 2018 , Duraj et al, 2021 ), both approaches link ATP production to mitochondrial metabolism. More importantly, there were marked metabolic differences between the two cell lines, consistent with different sensitivities to treatment previously reported ( McKelvey et al, 2021 ), and distinct histopathologic features of the respective tumors.…”

Genetically Encoded ATP Biosensors for Direct Monitoring of Cellular ATP Dynamics

“…There have been studies showing progressive remodeling of pathways in hiPSC-CMs during maturation, such as their increased ability to utilize fatty acids as a source of energy [ 103 , 104 ]. Current methodologies to test rates of glycolysis and OXPHOS include looking at aspects of metabolism such as lactate production [ 22 , 104 , 105 ], which is indicative of overall glycolysis. However, one of the downsides to these methods are that they are not direct, as the lactate is a byproduct of glycolysis.…”

“…Given the crucial role of energy metabolism, numerous methodologies have been developed and extensively used to gain a better understanding of the bioenergetic changes occurring within living cells [ 19 , 20 ]. Oxography is a technique that allows for high-resolution respirometric measurement of bioenergetics in permeabilized cells and isolated mitochondria in response to substrates, electron transport chain (ETC) complex inhibitors, and other metabolic effectors [ 21 , 22 ]. Oxygraphy measures oxygen (O 2 ) as a gas dissolved in an aqueous solution, monitoring oxygen consumption and flux over time within the sample.…”