Fig. 5: Bioenergetic and metabolic alterations in LOAD.
Summary of energy flow and substrate metabolism at bioenergetic “branch points” where changes in LOAD cells have been identified in this study. Upregulated processes are indicated in red and downregulated processes in blue. Production of NAD and NADH to transfer protons (H+) and electrons (e–) is reduced in LOAD cells (1). Glucose uptake and INS/IGF-1 signaling (2) are impaired and baseline glycolytic activities (3) are increased in LOAD cells; however, stimulation of glycolysis by glycolytic substrates is diminished. In addition, LOAD cells have reduced metabolism of lactate, a key metabolite produced by astrocytes and released for uptake by neurons to support energy production [13, 20, 22]. Lactate is converted from or can be converted to pyruvate that is the end product of glycolysis and metabolized in the mitochondria to Acetyl-CoA and oxaloacetate to fuel the Krebs cycle (4) that generates the reducing agents FADH2 and NADH, and ATP. LOAD cells have deficiencies in activating the Krebs cycle. Because glycolytically produced cytosolic NADH cannot pass the outer mitochondrial membrane, protons and electrons are transported through the G3P shuttle (5) and MAS (6) that generate FADH2 in the intermembrane space and NADH in the mitochondrial matrix, respectively. LOAD NPCs have diminished G3P shuttle activity and both LOAD NPCs and astrocytes exhibit increased activation of MAS. LOAD cells also have increased transport of fatty acids to the mitochondria through carnitine carriers and their metabolism in β-oxidation (7), as an alternative pathway to produce FADH2, NADH, ATP, and Acetyl-CoA. The protons and electrons carried by NADH and FADH2 are used to generate a proton gradient in the ETC (8), which includes complexes I-V, coenzyme Q, and cytochrome C, and leads to the production of ATP by OxPhos. In general, OxPhos is increased in LOAD cells; however, LOAD astrocytes have diminished direct substrate activation of complex I and II. Finally, the functional changes at these bioenergetic and metabolic “branch points” are associated with transcriptional changes of genes that are involved in these processes.
