Complex I deficiency disrupts postnatal neurogenesis in the subventricular zone in a mouse model of Leigh Syndrome

Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent patient studies suggest behavioral phenotypes more akin to neurodevelopment delays preceding degenerative regression of skills. Reevaluating a mouse model of LS that recapitulates key disease features, we show neurodevelopmental defects occur in the highly neurogenic subventricular zone (SVZ) region postnatally prior to neurodegenerative events. We demonstrate a reduced number of neural stem cells with less regenerative potential and stall in maturation throughout neurodevelopment. We employ single cell RNA sequencing technology to identify shifts in the neural stem cell progenitor lineage in LS mice and identify gene clusters responsible for the dysregulation of neurogenesis. We also demonstrate that cell cycle perturbations are partially responsible for deficits found in the SVZ. Given that LS is purely considered a neurodegenerative disease, we propose that mitochondrial diseases may have neurodevelopmental origins Overall design: For single-cell RNA sequencing, we isolated cells from the subventricular zone (SVZ) of wild-type and NDUFS4 knockout (KO) mice at postnatal day 14 (P14). A total of four samples were sequenced, including two wild-type and two NDUFS4 KO biological replicates