HPDL knockout mouse sequencing data
Mitochondrial neurodevelopmental disorders frequently affect energy-intensive tissues such as the brain. Their intricate genetic and metabolic origins complicate treatment strategies. HPDL, a mitochondrial-associated protein, has been implicated in various neurodevelopmental disorders, though its role remains poorly understood. Here, we investigate the impact of HPDL deficiency on brain development using a novel HPDL knockout (KO) mouse model generated via CRISPR/Cas9 technology. Comprehensive phenotypic, histological, transcriptomic, and metabolomic analyses were performed on postnatal day 7 HPDL KO and wild-type (WT) brain tissues. Synaptic function was evaluated through electrophysiological recordings, while protein expression was assessed by Western blotting. HPDL KO mice exhibited pronounced neurodevelopmental deficits, including reduced body size, increased oxidative stress, impaired myelination, and early mortality. Transcriptomic analysis identified 238 differentially expressed genes, with significant downregulation of glutamatergic synapse markers such as VGluT1. Metabolomics profiling highlighted disruptions in CoQ10 biosynthesis and fatty acid metabolism, indicating impaired oxidative phosphorylation. Electrophysiological recordings revealed reduced miniature excitatory postsynaptic current frequency, linking synaptic dysfunction to mitochondrial impairment. These findings establish HPDL as essential for mitochondrial integrity and proper brain development. Integrating transcriptomic and metabolomic data suggests potential therapeutic targets, including CoQ10 supplementation, for mitigating HPDL mutation effects in neurodevelopmental disorders. This work provides a foundation for metabolic interventions in mitochondrial diseases.