Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD
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Authors
Li, ShuangxiWu, Zhihao
Li, Yu
Tantray, Ishaq
De Stefani, Diego
Mattarei, Andrea
Krishnan, Gopinath
Gao, Fen-Biao
Vogel, Hannes
Lu, Bingwei
UMass Chan Affiliations
Department of NeurologyDocument Type
Journal ArticlePublication Date
2020-08-04Keywords
C9-ALS/FTDDPR; K(+)/H(+) antiporter
MICOS
Mic27/Apool
Opa1
cristae junction
mitochondrial K(+) homeostasis
muscle
nigericin
Cellular and Molecular Physiology
Molecular and Cellular Neuroscience
Nervous System Diseases
Neurology
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Show full item recordAbstract
Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, the contribution of the other cell types to the ALS phenotypes is understudied. G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS along with frontotemporal dementia (C9-ALS/FTD), with increasing evidence supporting repeat-encoded poly(GR) in disease pathogenesis. Here, we show in Drosophila muscle that poly(GR) enters mitochondria and interacts with components of the Mitochondrial Contact Site and Cristae Organizing System (MICOS), altering MICOS dynamics and intra-subunit interactions. This impairs mitochondrial inner membrane structure, ion homeostasis, mitochondrial metabolism, and muscle integrity. Similar mitochondrial defects are observed in patient fibroblasts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.Source
Li S, Wu Z, Li Y, Tantray I, De Stefani D, Mattarei A, Krishnan G, Gao FB, Vogel H, Lu B. Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD. Cell Rep. 2020 Aug 4;32(5):107989. doi: 10.1016/j.celrep.2020.107989. PMID: 32755582; PMCID: PMC7433775. Link to article on publisher's site
DOI
10.1016/j.celrep.2020.107989Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41536PubMed ID
32755582Related Resources
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Copyright 2020 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.celrep.2020.107989
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Except where otherwise noted, this item's license is described as Copyright 2020 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).