title: Lysyl-tRNA synthetase is a target for mutant SOD1 toxicity in mitochondria.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the motor neurons. The majority of familial forms of ALS are caused by mutations in the Cu,Zn-superoxide dismutase (SOD1). In mutant SOD1 spinal cord motor neurons, mitochondria develop abnormal morphology, bioenergetic defects, and degeneration. However, the mechanisms of mitochondrial toxicity are still unclear. One possibility is that mutant SOD1 establishes aberrant interactions with nuclear-encoded mitochondrial proteins, which can interfere with their normal trafficking from the cytosol to mitochondria. Lysyl-tRNA synthetase (KARS), an enzyme required for protein translation that was shown to interact with mutant SOD1 in yeast, is a good candidate as a target for interaction with mutant SOD1 at the mitochondrion in mammals because of its dual cytosolic and mitochondrial localization. Here, we show that in mammalian cells mutant SOD1 interacts preferentially with the mitochondrial form of KARS (mitoKARS). KARS-SOD1 interactions occur also in the mitochondria of the nervous system in transgenic mice. In the presence of mutant SOD1, mitoKARS displays a high propensity to misfold and aggregate prior to its import into mitochondria, becoming a target for proteasome degradation. Impaired mitoKARS import correlates with decreased mitochondrial protein synthesis. Ultimately, the abnormal interactions between mutant SOD1 and mitoKARS result in mitochondrial morphological abnormalities and cell toxicity. mitoKARS is the first described member of a group of mitochondrial proteins whose interaction with mutant SOD1 contributes to mitochondrial dysfunction in ALS.
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors: Hibiki
authors: H
authors: Kawamata
authors: Jordi
authors: J
authors: Magrané
authors: Catherine
authors: C
authors: Kunst
authors: Michael P
authors: MP
authors: King
authors: Giovanni
authors: G
authors: Manfredi
mesh_terms: D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008250:Lysine-tRNA Ligase / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex; D008250:Lysine-tRNA Ligase