RT Journal Article SR Electronic T1 Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson’s disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.17.476616 DO 10.1101/2022.01.17.476616 A1 Mallet, David A1 Goutaudier, Raphael A1 Barbier, Emmanuel L. A1 Carnicella, Sebastien A1 Colca, Jerry R. A1 Fauvelle, Florence A1 Boulet, Sabrina YR 2022 UL http://biorxiv.org/content/early/2022/01/20/2022.01.17.476616.abstract AB Background A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson’s disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160.Methods We investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics.Results MSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis.Conclusion MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.Competing Interest StatementThe authors have declared no competing interest.6-OHDA6-hydroxydopamineDSDorsal striatummTORMammalian target of rapamycinMPCMitochondrial pyruvate carrierMPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineNMRNuclear magnetic resonancePDParkinson’s diseaseSNcSubstantia nigra pars compactaTCATricarboxylic acidTH-IRTyrosine hydroxylase immunoreactivityTZDthiazolidinedione