SETD5 haploinsufficiency affects mitochondrial compartment in neural cells

Neurodevelopmental disorders (NDDs) are heterogeneous conditions due to alterations of a variety of molecular mechanisms and cell dysfunctions. Epigenetic basis of NDDs have been reported in an increasingly number of cases while mitochondrial dysfunctions are more common within NDD patients than in the general population. Here, we investigated experimental models of Setd5 haploinsufficiency, that leads to NDDs in humans due to chromatin defects, and uncovered that mitochondrial dysfunction participates in the pathogenesis. Mitochondrial impairment is facilitated by transcriptional aberrations that follow the decrease of SETD5 enzyme. Low levels of SETD5 resulted in fragmented mitochondria, less mitochondrial potential and ATP production both in neural precursors and neurons. Mitochondria were miss-localized in mutant neurons, with few organelles within neurites and synapses. Our study explores the epigenetics/mitochondria interplay as an important aspect of NDD pathophysiology and defines the impairments of mitochondrial functionality and dynamics as new therapeutic targets for disorders associated with loss of SETD5. RNA-seq of mouse Neural precursors cells cultured in High Oxygen condition