title: Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency.
abstract: Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kambiz N
authors.initials: KN
authors.lastname: Alavian
authors.forename: Steven I
authors.initials: SI
authors.lastname: Dworetzky
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanni
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Silvio
authors.initials: S
authors.lastname: Sacchetti
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mariggio
authors.forename: Marco
authors.initials: M
authors.lastname: Onofrj
authors.forename: Astrid
authors.initials: A
authors.lastname: Thomas
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Mangold
authors.forename: Armando P
authors.initials: AP
authors.lastname: Signore
authors.forename: Ulrike
authors.initials: U
authors.lastname: Demarco
authors.forename: Damon R
authors.initials: DR
authors.lastname: Demady
authors.forename: Panah
authors.initials: P
authors.lastname: Nabili
authors.forename: Emma
authors.initials: E
authors.lastname: Lazrove
authors.forename: Peter J S
authors.initials: PJ
authors.lastname: Smith
authors.forename: Valentin K
authors.initials: VK
authors.lastname: Gribkoff
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jonas
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000648:ultrastructure*; D009842:Oligopeptides / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D011433:Propranolol