Normal mitochondrial metabolism involves lysine uptake through the ornithine carrier (ORC1) with proton exchange. Lysine degradation is initiated by combination with α-ketoglutarate (α-KG) to form saccharopine. Dehydrogenation of saccharopine forms glutamate and aminoadipic semialdehyde, which is further oxidized to α-ketoadipate. Glutaryl-CoA is then formed from oxidation of α-ketoadipate with addition of free CoA. GCDH is required for complete oxidation with the formation of acetyl-CoA that can enter the Krebs cycle. GCDH deficiency results in disruption of normal lysine breakdown, which may cause saccharopine to accumulate and sequester α-KG. Alternatively, accumulating free glutaric acid (glutarate) may deplete α-KG levels by a strict counter-exchange mechanism via the oxodicarboxylate carrier (ODC) and to a lesser extent through the oxoglutarate carrier (OGC) that normally functions in the malate/aspartate shuttle. Depletion of α-KG prevents regeneration of oxaloacetate (OAA) needed to combine with acetyl-CoA to form citrate for continued Krebs cycle function. Acetyl-CoA is unable to enter the Krebs cycle and accumulates. CPTII, carnitine palmitoyltransferase II; PDH, pyruvate dehydrogenase.