Dhtkd1, encoding dehydrogenase E1 and transketolase domain containing 1, is a key part of the 2-ketoadipic acid dehydrogenase complex, involved in lysine and tryptophan catabolism [1]. It's essential for mitochondrial metabolism, playing a role in mitochondrial biogenesis and function maintenance, and thus is crucial for cell function, energy metabolism, and signal transduction [1,2].

In Dhtkd1 -/- mice, which mimic Charcot-Marie-Tooth disease (CMT) type 2 phenotypes, there are progressive weakness, atrophy in distal limb parts, motor and sensory dysfunctions, decreased nerve conduction velocity, along with severe metabolic abnormalities and increased levels of 2-ketoadipic acid and 2-aminoadipic acid in urine [1]. These findings suggest that loss of Dhtkd1 causes CMT2Q-like phenotypes through dysregulation of myelin-related proteins associated with elevated substrate and insulin levels [1]. Also, in HAP-1 cells with Dhtkd1 knock-out, there are impaired mitochondrial structure and function, yet normal cell proliferation is maintained potentially via compensatory mechanisms [3].

In conclusion, Dhtkd1 is vital for mitochondrial function and biogenesis. Mouse models with Dhtkd1 knock-out have revealed its role in CMT2 and provided insights into the pathogenesis of this peripheral neuropathy, as well as potential mechanisms in cardiometabolic disease [1,3].