Figure 4: Metabolism of tryptophan and lysine is impaired by mitochondrial oxodicarboxylate carrier deficiency.

(a) The degradation pathways of tryptophan and lysine run through the mitochondrion, which links it to the generation of adenosine triphosphate through the production of nicotinamide adenine dinucleotide plus hydrogen (NADH), which leads to the reduction of the co-enzyme Q (Q) via complex I, the production of acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle, and through the reduction of the Q pool directly via glutaryl-CoA dehydrogenase and the electron-transferring flavoprotein (dashed line). The metabolic model predicts an increase in quinolinic acid and picolinate levels, which are spontaneously (*) formed from semialdehydes, and in oxoadipate and pipecolate levels, because the import of 2-oxoadipate and 2-aminoadipate into mitochondria is blocked by mitochondrial oxodicarboxylate carrier deficiency (red arrows). These intermediates may have neurotoxic effects, leading to neuropathy. (b) Targeted metabolic analysis detected increased 2-oxoadipate, quinolinic acid, and pipecolic acid in the patient and in three other patients carrying DHTKD1 mutations. ADP, adenosine diphosphate; ATP, adenosine triphosphate; CxI, complex I (etc.); ETF, electron transfer flavoprotein; GCDH, glutaryl-CoA dehydrogenase; ODC, oxodicarboxylate carrier; AAC, ADP/ATP carrier; PiC, phosphate carrier; MPC, mitochondrial pyruvate carrier; Q, ubiquinone..