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.

An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1

“…We found that induction of oxidative stress by treating lymphoblasts with hydrogen peroxide (H 2 O 2 ) did not further increase the iperOxSOD1 oxidative state, although it did trigger iperOxSOD1 aggregation and formation of a toxic complex with mitochondrial Bcl-2, similar to the complex that we recently reported for fALS-linked mutSOD1 (19). Like mutSOD1 (20) and other toxic proteins (21,22), iperOxSOD1 induces a conformational change in Bcl-2 that exposes the toxic BH3 domain, damaging the lymphoblast mitochondria.…”

“…Thus, our data highlight the existence of a converging pathogenic pathway between a portion of fALS and sALS cases, leading to the possibility of subclassifying ALS based on the identification of specific biomarkers. Moreover, taken together with recent data showing that SOD1 can be targeted therapeutically in sporadic ALS (23), our finding that Bcl-2 becomes a toxic target of iperOxSOD1 through the same mechanism as mutSOD1 (20) can permit the design of target-based therapies against the SOD1/Bcl-2 complex with efficacy possibly exceeding that of therapies for the small percentage of patients with mutSOD1.…”

“…that mutSOD1 relies on this interaction to damage the mitochondria (20). We also showed that formation of the toxic mutSOD1/Bcl-2 complex is mitochondria-specific and driven by conformational changes of the unstable mutSOD1 (20).…”

“…We also showed that formation of the toxic mutSOD1/Bcl-2 complex is mitochondria-specific and driven by conformational changes of the unstable mutSOD1 (20). Consequently, we conducted co-immunoprecipitation experiments to determine whether iperOxSOD1 aberrantly binds with Bcl-2 in mitochondria from iperOxSOD1-sALS patients.…”

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

“…In these diseases and others, the formation of amyloid plaques, often observed post mortem, has long been thought to play a role in neurodegeneration, but toxicity has never been confirmed (1)(2)(3). Recent research has shown that small, soluble oligomers, rather than insoluble amyloids, are likely to be the cytotoxic species causing neurodegeneration (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These small, soluble oligomers undergo aberrant interactions with cell machinery and activate cell death pathways, but their exact stoichiometry is not known and their properties have yet to be characterized.…”