title: ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2.
abstract: In mutant superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS), accumulation of misfolded mutant SOD1 in spinal cord mitochondria is thought to cause mitochondrial dysfunction. Whether mutant SOD1 is toxic per se or whether it damages the mitochondria through interactions with other mitochondrial proteins is not known. We previously identified Bcl-2 as an interacting partner of mutant SOD1 specifically in spinal cord, but not in liver, mitochondria of SOD1 mice and patients. We now show that mutant SOD1 toxicity relies on this interaction. Mutant SOD1 induces mitochondrial morphological changes and compromises mitochondrial membrane integrity leading to release of Cytochrome C only in the presence of Bcl-2. In cells, mouse and human spinal cord with SOD1 mutations, the binding to mutant SOD1 triggers a conformational change in Bcl-2 that results in the uncovering of its toxic BH3 domain and conversion of Bcl-2 into a toxic protein. Bcl-2 carrying a mutagenized, non-toxic BH3 domain fails to support mutant SOD1 mitochondrial toxicity. The identification of Bcl-2 as a specific target and active partner in mutant SOD1 mitochondrial toxicity suggests new therapeutic strategies to inhibit the formation of the toxic mutant SOD1/Bcl-2 complex and to prevent mitochondrial damage in ALS.
authors.affiliation: Frances and Joseph Weinberg Unit for ALS Research, Farber Institute for Neurosciences, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Pedrini
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Stefania
authors.initials: S
authors.lastname: Guareschi
authors.forename: Marina
authors.initials: M
authors.lastname: Bogush
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Nicole
authors.initials: N
authors.lastname: Naniche
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kia
authors.forename: Davide
authors.initials: D
authors.lastname: Trotti
authors.forename: Piera
authors.initials: P
authors.lastname: Pasinelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D050505:Mutant Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000633:toxicity; D013482:Superoxide Dismutase / Q000235:genetics* / Q000633:toxicity
chemical_list: D050505:Mutant Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013482:Superoxide Dismutase
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