Inhibition of mitochondrial transcription by the neurotoxin MPP

Abstract

The neurotoxin MPP⁺ triggers cell death of dopamine neurons and induces Parkinson's disease symptoms in mice and men, but the immediate transcriptional response to this neurotoxin has not been studied. We therefore treated human SH-SY5Y cells with a low dose (0.1 mM) of MPP⁺ and measured the effect on nascent transcription by precision run-on sequencing (PRO-seq). We found that transcription of the mitochondrial genome was significantly reduced already after 30 min, whereas nuclear gene transcription was unaffected. Inhibition of respiratory complex I by MPP⁺ led to reduced ATP production, that may explain the diminished activity of mitochondrial RNA polymerase. Our results show that MPP⁺ has a direct effect on mitochondrial function and transcription, and that other gene expression or epigenetic changes induced by this neurotoxin are secondary effects that reflect a cellular adaptation program.

Keywords: ATP; Mitochondria; Neurotoxin; Parkinson's disease; Respiration; Transcription.