Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure

Abstract

We tested how the addition of oxaloacetate (OAA) to SH-SY5Y cells affected bioenergetic fluxes and infrastructure, and compared the effects of OAA to malate, pyruvate, and glucose deprivation. OAA displayed pro-glycolysis and pro-respiration effects. OAA pro-glycolysis effects were not a consequence of decarboxylation to pyruvate because unlike OAA, pyruvate lowered the glycolysis flux. Malate did not alter glycolysis flux and reduced mitochondrial respiration. Glucose deprivation essentially eliminated glycolysis and increased mitochondrial respiration. OAA increased, while malate decreased, the cell NAD+/NADH ratio. Cytosolic malate dehydrogenase 1 (MDH1) protein increased with OAA treatment, but not with malate or glucose deprivation. Glucose deprivation increased protein levels of ATP citrate lyase, an enzyme which produces cytosolic OAA, while OAA altered neither ATP citrate lyase mRNA nor protein levels. OAA, but not glucose deprivation, increased COX2, PGC1α, PGC1β, and PRC protein levels. OAA increased total and phosphorylated SIRT1 protein. We conclude that adding OAA to SH-SY5Y cells can support or enhance both glycolysis and respiration fluxes. These effects appear to depend, at least partly, on OAA causing a shift in the cell redox balance to a more oxidized state, that it is not a glycolysis pathway intermediate, and possibly its ability to act in an anaplerotic fashion.

Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism

“…OAA has been described as a potent neuroprotectant because of its role as a glutamate scavenger, which is an important mediator of neuronal degeneration . In a cell line derived from a human neuroblastoma, OAA was found to increase the glycolytic flux and NAD/NADH ratio . OAA is also known to attenuate zinc‐induced cell death in both retinal pigmented epithelium and insulinoma cells .…”

“…(42) In a cell line derived from a human neuroblastoma, OAA was found to increase the glycolytic flux and NAD/NADH ratio. (43) OAA is also known to attenuate zinc-induced cell death in both retinal pigmented epithelium and insulinoma cells. (44) Although specific pathways have not yet been clearly defined, OAA is potentially associated with increased cell viability and mitochondria preservation, but also antioxidative effects.…”

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

“…Further, OAA treatment achieved broader beneficial effects in the brain, including insulin pathway activation, neurogenesis, and reduced neuroinflammatory markers (Wilkins et al, ). When tested on SH‐SY5Y neuroblastoma cells, OAA enhanced glycolysis and cell respiration, and this correlated with an increased NAD+/NADH ratio (Wilkins et al, ). As mentioned above, OAA is being tested in a Phase 1b clinical trial in AD subjects (NCT02593318; Table ).…”

New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders

“…OAA can also be converted to phosphoenolpyruvate (PEP) within the cytoplasm as a part of gluconeogenesis. In vitro studies have found that OAA supports glycolysis and mitochondrial respiration fluxes, promotes expression of mitochondrial biogenesis proteins (PGC1α) and enhances SIRT1 phosphorylation [129]. In vivo studies have shown that intraperitoneal injection of OAA in 4-month old C57Bl/6 male mice for two weeks enhances brain bioenergetic pathway protein expression and neurogenesis markers.…”