Dichloroacetate Stabilizes Mitochondrial Fusion Dynamics in Models of Neurodegeneration

Darren O'Hara; Gavin M Davis; Natalie A Adlesic; Jerrard M Hayes; Gavin P Davey

doi:10.3389/fnmol.2019.00219

Dichloroacetate Stabilizes Mitochondrial Fusion Dynamics in Models of Neurodegeneration

Front Mol Neurosci. 2019 Sep 18:12:219. doi: 10.3389/fnmol.2019.00219. eCollection 2019.

Authors

Darren O'Hara¹, Gavin M Davis¹, Natalie A Adlesic¹, Jerrard M Hayes¹, Gavin P Davey¹

Affiliation

¹ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

Abstract

Mitochondrial dysfunction is a recognized hallmark of neurodegenerative diseases and abnormal mitochondrial fusion-fission dynamics have been implicated in the pathogenesis of neurodegenerative disorders. This study characterizes the effects of metabolic flux inhibitors and activators on mitochondrial fusion dynamics in the neuronal cell culture model of differentiated PC12 cells. Using a real time confocal microscopy assay, it was found that the carnitine palmitoyltransferase I (CPTI) inhibitor, etomoxir, reduced mitochondrial fusion dynamics in a time-dependent manner. Etomoxir also decreased JO₂, ΔΨ_m and reactive oxygen species (ROS) production rates. The mitochondrial pyruvate carrier (MPC) inhibitor, UK5099, reduced fusion dynamics and in combination with etomoxir these inhibitory effects were amplified. Use of the pyruvate dehydrogenase (PDH) kinase inhibitor dichloroacetate, which is known to increase metabolic flux through PDH, reversed the etomoxir-induced effects on fusion dynamics, JO₂, ΔΨ_m but not ROS production rates. Dichloroacetate also partially reversed inhibition of mitochondrial fusion dynamics caused by the parkinsonian-inducing neurotoxin, MPP⁺. These results suggest that dichloroacetate-induced activation of metabolic flux in the mitochondrion may be a mechanism to restore normal mitochondrial fusion-fission dynamics in metabolically challenged cells.

Keywords: MPP+; Parkinson’s disease; carnitine palmitoyl transferase; fusion-fission dynamics; mitochondria; mitochondrial pyruvate carrier; pyruvate dehydrogenase kinase.