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Published on: June 30, 2023
Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD
Shuangxi Li1, Zhihao Wu1, Yu Li1
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
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.
Insights
Poly(GR) from C9ORF72 repeat expansions enters mitochondria in ALS, disrupting the MICOS complex and causing muscle damage. Restoring mitochondrial ion balance offers a potential therapeutic strategy for C9-ALS/FTD.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron and other cell type pathology.
- C9ORF72 repeat expansion is a common genetic cause of ALS and frontotemporal dementia (C9-ALS/FTD).
- Poly(GR) peptides encoded by the repeat expansion are implicated in disease pathogenesis.
Purpose of the Study:
- Investigate the role of poly(GR) in cellular pathology beyond motor neurons.
- Elucidate the molecular mechanisms by which poly(GR) affects cellular function.
- Identify potential therapeutic targets for C9-ALS/FTD.
Main Methods:
- Utilized Drosophila muscle and patient-derived fibroblasts as model systems.
- Examined the interaction of poly(GR) with mitochondrial components, specifically the MICOS complex.
- Assessed mitochondrial structure, function, metabolism, and muscle integrity.
- Tested genetic and pharmacological interventions to rescue pathology.
Main Results:
- Poly(GR) enters mitochondria and disrupts the MICOS complex, altering its dynamics and interactions.
- Mitochondrial inner membrane structure, ion homeostasis, and metabolism are impaired.
- Muscle integrity is compromised in Drosophila models.
- Similar mitochondrial defects are observed in patient fibroblasts.
- Genetic modulation of MICOS and nigericin treatment rescued mitochondrial pathology and disease phenotypes.
Conclusions:
- Poly(GR)-induced mitochondrial dysfunction is a key pathogenic mechanism in C9-ALS/FTD.
- MICOS-regulated ion homeostasis is critical in C9-ALS pathogenesis.
- Targeting mitochondrial ion homeostasis presents a promising therapeutic avenue for C9-ALS/FTD.
