UMMS Affiliation

Department of Neurology

Publication Date

2020-08-04

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology

Abstract

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.

Keywords

C9-ALS/FTD, DPR; K(+)/H(+) antiporter, MICOS, Mic27/Apool, Opa1, cristae junction, mitochondrial K(+) homeostasis, muscle, nigericin

Rights and Permissions

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/).

DOI of Published Version

10.1016/j.celrep.2020.107989

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

Journal/Book/Conference Title

Cell reports

Related Resources

Link to Article in PubMed

PubMed ID

32755582

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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