HPDL (4-hydroxyphenylpyruvate dioxygenase like) is a mitochondrial iron-dependent dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate to 4-hydroxymandelate (4-HMA) as part of the coenzyme Q10 biosynthesis pathway 1. This enzyme represents a crucial step in CoQ10 headgroup synthesis, where 4-HMA serves as an intermediate for producing 4-hydroxybenzoate, the CoQ10 headgroup precursor 1. HPDL also participates in alternative leucine metabolism pathways in immune cells, contributing to β-hydroxy β-methylbutyric acid production that regulates Th17 responses via the mTORC1-HIF1α pathway 2. Biallelic HPDL variants cause severe neurodevelopmental disorders characterized by progressive spasticity, brain white matter abnormalities, developmental delay, seizures, and brain atrophy 34. These conditions result from disrupted CoQ10 synthesis leading to mitochondrial dysfunction, altered oxidative metabolism, and increased reactive oxygen species 4. Remarkably, therapeutic intervention with CoQ10 headgroup intermediates 4-HMA and 4-HB can restore CoQ10 synthesis and ameliorate disease symptoms, with both compounds enabling 90-100% survival in HPDL-deficient mice and improving neurological symptoms in human patients 5. This discovery provides a mechanistic treatment approach for HPDL-related mitochondrial encephalopathies through bypass therapy targeting the disrupted biosynthetic pathway.