Mitochondria drive neuronal differentiation by metabolising nuclear-encoded RNA [ATAC-seq]

In this study, we show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of the nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (Pnpt1) residing in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, phosphorolysis by Pnpt1 indirectly suppresses ATP production by depriving ATP synthase of inorganic phosphate, resulting in delayed recovery of the attenuated transcriptomic memory. Collectively, these events force the progenitor cells towards a “tipping point” characterised by emergence of a competing neuronal differentiation program. ATAC-seq profiles of NPCs at baseline, 1h post induction of differentiation, and 2h post-induction of differentiation, Biological replicates: 1/group