PD MIN analysis, 3/9/2020 12:32 PM 1 Mitochondria-mitochondria interaction networks show altered topological patterns in Parkinson’s disease 1 , Instituto de (UIB-CSIC), E-07122 Palma de Mallorca, Spain. 2 , Center for Biomedical Technology, Universidad Politécnica de Madrid, Campus of Montegancedo, E- 28223 Pozuelo de Alarcón, Madrid, Spain. 3 , LCSB (Luxembourg Centre for Systems Biomedicine), University of Luxembourg, Campus Belval, 6, Avenue du Swing, L-4367 Belvaux, Luxembourg. 4 , Department of Infection and Immunity, Luxembourg Institute of Health (LIH), 29, rue Henri Koch, L- 4354 Esch-sur-Alzette, Luxembourg. 5 , Centre Hospitalier de Luxembourg (CHL), 4, Rue Nicolas Ernest Barblé, 1210 Luxembourg, Luxembourg. 6 , Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), University of Southern Denmark, 5000 C, Odense, Denmark. 7 , Transversal Translational Medicine, Luxembourg Institute of Health (LIH), 1A-B, rue Thomas Edison, L- 1445 Strassen, Luxembourg *Correspondence should be addressed to F.Q.H. (Feng.he@lih.lu ). SUMMARY Mitochondrial dysfunction is linked to pathogenesis of Parkinson’s disease (PD). However, individual-mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria-mitochondria interaction networks (MINs). Here we showed that MINs form non-classical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients, however, altered topological patterns are observed in PD patients. These patterns highly correlate with PD clinical scores and a machine-learning approach based on the MIN features accurately distinguish between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also display specific changes. CRISPR/CAS9-based genome correction of alpha- synuclein point mutations reverses the changes in MINs of mDANs. Our MIN network analysis opens a new dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation. . CC-BY-NC-ND 4.0 International license (which was not certified by peer review) is the author/funder. It is made available under a The copyright holder for this preprint this version posted March 10, 2020. . https://doi.org/10.1101/2020.03.09.984195 doi: bioRxiv preprint