Troglitazone Regulates Anaplerosis via a Pull/Push Affect on Glutamate Dehydrogenase Mediated Glutamate Deamination in Kidney-derived Epithelial Cells; Implications for the Warburg Effect

Abstract

Mitochondrial Krebs cycle keto acid pool depends upon input from pyruvate and glutamate to maintain homeostasis. We studied the affect of glucose-derived pyruvate removal on compensatory input from glutamine-derived glutamate by accelerated glutamate metabolism via glutamate dehydrogenase (GDH). In glutamine minus glucose media (Gln-Glc), NH₄⁺ production increased 41% without an increase in glutamine uptake consistent with accelerated glutamate metabolism via GDH. Alanine production dropped 40% consistent with a shift of glutamate from alanine aminotransferase (ALT) to GDH. Troglitazone (TRO) added to the Gln-Glc media further enhanced glutamate metabolism via GDH at the expense of glutamate metabolism via ALT since alanine production dropped an additional 70%. TRO reduced cell glutamate content 30% while increasing lactate production 5-fold consistent with blocking of cytosolic pyruvate formed from mitochondrial malate from reentering the cycle and maintaining keto acid pool homeostasis. Consequently mitochondrial keto acid pool deficit pulls glutamate via GDH into the cycle. Additionally TRO reduced cytosolic pH which effectively pushes glutamate via GDH, rather than merely shifting glutamate from ALT to GDH. Providing intramitochondrial pyruvate in the form of methyl pyruvate reduced glutamate metabolism via GDH and elevated glutamate metabolism via ALT to control levels restoring acid-base balance. Our findings are consistent with TRO regulation of anaplerosis dependent upon dual pull (cycle keto-acid deficit)/push (cytosolic acidosis) mechanisms.

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical response and survival: a study of human biochemical individuality

“…Increases in the “glutamate pulling effect” have been described under conditions of metabolic stress induced by glucose deprivation [ 15 ]. In agreement, we found a significant ( p = 0.003, FDR = 0.009) inverse correlation between patient blood hexoses concentrations and the values of our breast cancer equation {[PC aa 36:6/[(Val/Phe)/Taurine]/C10:2} (Figure 1M ).…”

Identification of a dCache-type chemoreceptor in Campylobacter jejuni that specifically mediates chemotaxis towards methyl pyruvate

“…orientalis (Ramírez-Paredes et al, 2017), improves the growth of C. jejuni by acting as a donor for the tricarboxylic acid cycle, and restores the persister cells of E. coli O157:H7 by stimulating metabolism as the sole carbon source (Chen et al, 2021). In some eukaryotic cells, methyl pyruvate supplies intramitochondrial pyruvate, reduces glutamate metabolism through glutamate dehydrogenase, and improves glutamate metabolism through alanine aminotransferase (to control the acid-base balance) (Oliver et al, 2010). Moreover, in rat pancreatic islets, methyl pyruvate is the substrate of lactate dehydrogenase and alanine aminotransferase, and can be converted directly into amino acids for cell utilization, displaying a higher metabolic efficiency than pyruvate (Jijakli et al, 1996) The effects of toluene and quinoline on the chemotaxis of E. coli expressing the hybrid chemoreceptor Tlp342Tar200 to methyl pyruvate.…”