Figure 7. βOHB metabolism and effects in aralar-KO neurons and oligodendrocytes. βOHB metabolism leads to the synthesis of acetyl-CoA (AcCoA) and citrate which may be transported to the cytosol through the citrate carrier (CIC/Slc25a1). Citrate is converted to OAA through ACL reaction. Under conditions of high cytosolic NADH/NAD+ ratio as prevail in aralar-KO neurons (Pardo et al., 2006), a large fraction of OAA will be converted to malate (Mal) through malate DH reaction (cMDH) supplying the counter substrate for CIC to provide a citrate-malate redox shuttle (Palmieri, 2004; Pardo and Contreras, 2012). However, some of the OAA is also used in cytosolic Asp synthesis possibly through inverted Asp aminotransferase (cAAT) reaction, driven by the very low Asp levels (and also α-KG levels; Contreras et al., unpublished data) in aralar-KO neurons and retinas. The citrate-malate shuttle provides cytosolic AcCoA for NAA synthesis through Asp-NAT. This βOHB-induced NAA formed might serve as a precursor for myelin lipid synthesis in oligodendrocytes. Additionally, in the dopaminergic terminals, enhanced mitochondrial NADH production by βOHB would increase the GSH/GSSG ratio, reduce H2O2 levels and favor vesicular DA internalization through increased VMAT2 levels, avoiding its cytosolic oxidation occurring in aralar-KO mice (Llorente-Folch et al., 2013b). AcAc, acetoacetate; AcAc-CoA, acetoacetyl coenzyme A; ACAT, AcCoA C-acetyltransferase; Aralar, Asp-glutamate carrier isoform 1 (AGC1); BDH, b-hydroxybutyrate dehydrogenase; CoA, coenzyme A; CoQ, coenzyme Q; CytC, cytochrome C; DOPAC, 3,4-dihydroxyphenylacetic acid; Glu, glutamate; GPx, GSH peroxidase; GSH, glutathione; GSSG, GSH disulfure; MAO, monoamine oxidase; mMDH, mitochondrial malate dehydrogenase; MPC, mitochondrial pyruvate carrier; SCOT, succinyl-CoA-3-oxaloacid CoA transferase; Succ, succinate; Succ-CoA, succinil coenzyme A; TCA, tricarboxylic acid cycle; VMAT2, vesicular monoamine transporter 2; βOHB, β-hydroxybutyrate. Image created with BioRender.com.