Human Molecular Genetics Advance Access originally published online on September 24, 2009
Human Molecular Genetics 2009 18(23):4552-4564; doi:10.1093/hmg/ddp421
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Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities
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Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA
* To whom correspondence should be addressed at: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 E. 68th Street, A-505, New York, NY 10065, USA. Tel: +1 2127464605; Fax: +1 2127468276; Email: gim2004{at}med.cornell.edu
Received May 29, 2009; Accepted August 28, 2009
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by motor neuron degeneration. Mutations in Cu,Zn-superoxide dismutase (SOD1) are responsible for 20% of familial ALS cases via a toxic gain of function. In mutant SOD1 transgenic mice, mitochondria of spinal motor neurons develop abnormal morphology, bioenergetic defects and degeneration, which are presumably implicated in disease pathogenesis. SOD1 is mostly a cytosolic protein, but a substantial portion is associated with organelles, including mitochondria, where it localizes predominantly in the intermembrane space (IMS). However, whether mitochondrial mutant SOD1 contributes to disease pathogenesis remains to be elucidated. We have generated NSC34 motor neuronal cell lines expressing wild-type or mutant SOD1 containing a cleavable IMS targeting signal to directly investigate the pathogenic role of mutant SOD1 in mitochondria. We show that mitochondrially-targeted SOD1 localizes to the IMS, where it is enzymatically active. We prove that mutant IMS-targeted SOD1 causes neuronal toxicity under metabolic and oxidative stress conditions. Furthermore, we demonstrate for the first time neurite mitochondrial fragmentation and impaired mitochondrial dynamics in motor neurons expressing IMS mutant SOD1. These defects are associated with impaired maintenance of neuritic processes. Our findings demonstrate that mutant SOD1 localized in the IMS is sufficient to determine mitochondrial abnormalities and neuronal toxicity, and contributes to ALS pathogenesis.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Department of Pharmacology, University of Navarra, Pamplona, Spain.
Present address: URA CEA-CNRS 2210, Service MIRCen, Institut d'Imagerie Biomédicale, CEA, Fontenay aux Roses, France.