PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function

Abstract

word count: 266 2 AbstractMitochondrial dysfunction contributes to the pathogenesis of Parkinson's disease but it is not clear why inherent mitochondrial defects lead specifically to the death of dopaminergic neurons of the mid brain. PINK1 is mitochondrial kinase and PINK1 mutations cause early onset Parkinson's disease.We found that in neuronal progenitors, PINK1 regulates mitochondrial morphology, mitochondrial contact to the endoplasmic reticulum (ER) and the phosphorylation of Miro1. A compensatory metabolic shift towards lipid synthesis provides mitochondria with the components needed for membrane renewal and oxidative phosphorylation, maintaining the mitochondrial network once mature.Cholesterol is increased by loss of PINK1, promoting overall membrane rigidity. This alters the distribution of phosphorylated DAT at synapses and impairs dopamine uptake. PINK1 is required for the phosphorylation of tyrosine hydroxylase at Ser19, dopamine and calcium homeostasis and dopaminergic pacemaking.We suggest a novel mechanism for PINK1 pathogenicity in Parkinson's disease in addition to but not exclusive of mitophagy. We also provide a basis for potential therapeutics by showing that low doses of the cholesterol depleting drug ßcyclodextrin reverse PINK1-specific phenotypes.Gurion University of the Negev, Beer-Sheva, 8410501 Israel who developed the constructs for performing the BRET experiments for measurement of mitochondrial-ER contacts and kindly shared them with HFR and AG. Gerrit Machetanz of the

Role of Mitochondria–ER Contact Sites in Mitophagy

“…The contacts between mitochondria and ER are the locations for the synthesis of sphingolipids, and contain high levels of these lipids, as well as they are rich in cholesterol [ 131 , 202 , 203 ]. Recently, cholesterol levels have been tied to PINK1 biology and to defective mitophagy in Alzheimer’s disease [ 204 , 205 ]. Future research will determine if the lipid composition at MERCS is important for the formation of the mitophagophore and how this interplays with the proteins mediating mitophagy initiation.…”