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Mitochondria-mitochondria Interaction Networks Show Altered Topological Patterns In Parkinson’s Disease

Massimiliano Zanin, Bruno F. R. Santos, Paul M.A. Antony, Clara Berenguer-Escuder, Simone B. Larsen, Zoé Hanss, Peter Barbuti, Aidos S. Baumuratov, Dajana Grossmann, Christophe Capelle, Joseph Weber, Rudi Balling, Markus Ollert, Rejko Krüger, Nico J. Diederich, Feng Q. He

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SUMMARYMitochondrial 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.