ArticleHuman molecular genetics2010
ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2.
Article in Human molecular genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 154 citations in OpenAlex.
- Oxidative stress and inflammation in neurodegenerative disorders.Archives of toxicology · 2026Review
- Genetic contributions to mitochondrial dysfunction in amyotrophic lateral sclerosis etiology.HGG advances · 2026Article
- Impaired nucleocytoplasmic transport in SOD1-mediated ALS.Molecular neurodegeneration · 2026Article
- Mitochondria-ER contact sites in neurological disorders.Animal cells and systems · 2026Review
- Therapeutic mechanistic framework of mesenchymal stem cell-derived extracellular vesicles in neurodegenerative diseases.Extracellular vesicles and circulating nucleic acids · 2026Review
- Investigation of mitochondrial phenotypes in motor neurons derived by direct conversion of fibroblasts from familial ALS subjects.Cell death & disease · 2025Article
- Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?International journal of molecular sciences · 2025Review
- Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model.Acta neuropathologica communications · 2025Article
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
- A Sensitive and Versatile Cell-Based Assay Combines Luminescence and Trapping Approaches to Monitor Unconventional Protein Secretion.Traffic (Copenhagen, Denmark) · 2025Article
- Review
- Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model.Acta neuropathologica · 2025Article
- Using ALS to understand profilin 1's diverse roles in cellular physiology.Cytoskeleton (Hoboken, N.J.) · 2025Review
- Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.Frontiers in pharmacology · 2025Review
- Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Role of VDAC1 in hepatocyte apoptosis during acute liver injury in rats induced by obstructive jaundice.Iranian journal of basic medical sciences · 2025Article
- VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.Biomolecules · 2024Review
- Article
- Review
- miRNA profiling as a complementary diagnostic tool for amyotrophic lateral sclerosis.Scientific reports · 2023Article
32 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.