The UPR ^ER governs the cell-specific response of human dopaminergic neurons to mitochondrial stress

Mitochondrial dysfunction is thought to be central to the pathophysiology of Parkinson’s disease. The preferential vulnerability of dopaminergic (DA) neurons of the substantia nigra pars compacta to mitochondrial stress may underlie their massive degeneration and the occurrence of motor symptoms. Using LUHMES-derived DA neurons, we demonstrated that inhibition of the mitochondrial electron transport chain resulted in a severe alteration of mitochondrial turnover, pushing the balance towards mitochondrial loss, a reduction of the maturation status of the DA population and an increased proportion of apoptotic cells. PERK-mediated Unfolded Protein Response of the Endoplasmic Reticulum (UPR ^ER ) emerged as the key coordinator of the stress response, governing the inactivation of the mitochondrial UPR (UPR ^mt ), the initiation of mitophagy and the cell-specific expression of long non-coding RNAs (lncRNAs). Importantly, we discovered novel lncRNAs specifically expressed in human DA neurons upon stress. Among them, we showed that lnc-SLC6A15-5 contributes to the resumption of translation after mitochondrial stress.